Purine derivatives

ABSTRACT

The present invention relates to compounds of the formula  
                 
 
     and pharmaceutically acceptable salts and solvates thereof, to processes for the preparation of, intermediates used in the preparation of, and compositions containing such compounds and the uses of such compounds as adenosine A2a receptor agonists.

[0001] This application is a continuation of copending prior filedforeign application Great Britain Serial No. 0015727.1, filed Jun. 27,2000 (Attorney Docket No. PC10920), the benefit of the filing date ofwhich is claimed, and which is incorporated herein by reference in itsentirety; and is a continuation of prior filed provisional applicationU.S. Ser. No. 60/218,466, filed Jul. 14, 2000 (Attorney Docket No.PC10920), the benefit of the filing date of which is claimed, and whichis incorporated herein by reference in its entirety.

[0002] This invention relates to purine derivatives. More particularly,this invention relates to2-aminoalkyl-9-(tetrahydro-2-furanyl)-9H-purine derivatives and toprocesses for the preparation of, intermediates used in the preparationof, compositions containing and the uses of, such derivatives.

[0003] These derivatives are selective, functional agonists of the humanadenosine A2a receptor and may be used as anti-inflammatory agents inthe treatment of, inter alia, diseases of the respiratory tract.

[0004] Adenosine is a ubiquitous molecule having a central role inmammalian intermediary metabolism. Independently, adenosine acts onmultiple surface receptors to produce a variety of responses. Adenosinereceptor classification has revealed the presence of at least foursubtypes: A1, A2a, A2b and A3. Stimulation of adenosine A2 receptors onthe surface of human neutrophils has been reported to potently inhibit arange of neutrophil functions. Activated neutrophils can damage lungtissue by release of reactive oxygen species, for example, superoxideanion radicals (O₂ ⁻.), and granule products, for example, humanneutrophil elastase (HNE), amongst other inflammatory mediators. Inaddition, activated neutrophils perform both de novo synthesis andrelease of arachidonate products such as leukotriene B₄ (LTB₄). LTB₄ isa potent chemo-attractant that recruits additional neutrophils to theinflammatory focus, whereas released O₂ ⁻. and HNE adversely affect thepulmonary extracellular matrix. The A2 receptor subtype mediating manyof these responses (O₂ ⁻. and LTB4/HNE release and cell adhesion) isestablished as A2a. The A2 subtype (A2a or A2b) mediating the othereffects remains to be established.

[0005] Selective agonist activity at the A2a receptor is considered tooffer greater therapeutic benefit than the use of non-selectiveadenosine receptor agonists because interaction with other subtypes isassociated with detrimental effects in the lung in animal models andhuman tissue studies. For example, asthmatics, but not non-asthmatics,bronchoconstrict when challenged with inhaled adenosine. This responseis at least in part due to the activation of the A1 receptor subtype.Activation of A1 receptors also promotes neutrophil chemotaxis andadherence to endothelial cells, thus promoting lung injury. Furthermore,many patients with respiratory disease will be co-prescribedβ2-agonists, and negative interaction has been shown in animal studiesbetween isoprenaline and adenosine receptors negatively coupled toadenylate cyclase. Degranulation of human mast cells is promoted byactivation of adenosine A2b receptors, thus selectivity over the A2breceptor is also advantageous.

[0006] We have now surprisingly found the present purine derivativesinhibit neutrophil function and are selective agonists of the adenosineA2a receptor. They may also have antagonist activity at the adenosine A3receptor. The present compounds may be used to treat any disease forwhich an adenosine A2a receptor agonist is indicated. They can be usedto treat a disease where leukocyte (e.g. neutrophil, eosinophil,basophil, lymphocyte, macrophage)-induced tissue damage is implicated.They are useful as anti-inflammatory agents in the treatment of diseasesof the respiratory tract such as adult respiratory distress syndrome(ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonarydisease, cystic fibrosis, asthma, emphysema, bronchiectasis, chronicsinusitis and rhinitis. The present compounds may also be used in thetreatment of septic shock, male erectile dysfunction, hypertension,stroke, epilepsy, cerebral ischaemia, peripheral vascular disease,post-ischaemic reperfusion injury, diabetes, rheumatoid arthritis,multiple sclerosis, psoriasis, dermatitis, allergic dermatitis, eczema,ulcerative colitis, Crohns disease, inflammatory bowel disease,Heliobacter pylori gastritis, non-Heliobacter pylori gastritis,non-steroidal anti-inflammatory drug-induced damage to thegastrointestinal tract or a psychotic disorder, or for wound healing.

[0007] Accordingly, the present invention provides a compound of theformula

[0008] or a pharmaceutically acceptable salt or solvate thereof, wherein

[0009] R¹ is (i) H, (ii) C₁-C₆ alkyl optionally substituted by 1 or 2substituents each independently selected from phenyl, naphthyl andfluorenyl, said phenyl, naphthyl and fluorenyl being optionallysubstituted by C₁-C₆ alkyl, C₁-C₆ alkoxy, halo or cyano, or (iii)fluorenyl;

[0010] R²is H or C₁-C₆ alkyl;

[0011] either, R³ and R⁴, taken together with the nitrogen atom to whichthey are attached, represent azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, homopiperidinyl or homopiperazinyl, each being optionallysubstituted on a ring nitrogen or carbon atom by C₁-C₆ alkyl or C₃-C₈cycloalkyl and optionally substituted on a ring carbon atom not adjacentto a ring nitrogen atom by —

[0012] NR⁶R⁷ or —OR⁹,

[0013] or, R³ is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl or benzyl, said C₁-C₆alkyl being optionally substituted by C₃-C₈ cycloalkyl, and R⁴ is

[0014] (a) C₁-C₆ alkyl, C₃-C₈ cycloalkyl or R ⁵, said C₁-C₆ alkyl beingoptionally substituted by R¹⁵; or

[0015] (b) —(C₂-C₆ alkylene)-R⁸, or

[0016] (c) —(C₁-C₆ alkylene)-R¹³;

[0017] R⁵ is —CH₂OH or —CONR¹⁴R¹⁴;

[0018] R⁶ and R⁷ are either each independently H or C₁-C₆ alkyl or,taken together with the nitrogen atom to which they are attached,represent azetidinyl, pyrrolidinyl or piperidinyl, said azetidinyl,pyrrolidinyl and piperidinyl being optionally substituted by C₁-C₆alkyl;

[0019] R⁸ is (i) azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl,morpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homopiperazin-1-ylor tetrahydroisoquinolin-1-yl, each being optionally substituted on aring carbon atom by C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, C₁-C₆alkoxy-(C₁-C₆)-alkyl, R⁹R⁹N—(C₁-C₆)-alkyl, fluoro-(C₁-C₆)-alkyl,—CONR⁹R⁹, —COOR⁹ or C₂-C₅ alkanoyl, optionally substituted on a ringcarbon atom not adjacent to a ring nitrogen atom byfluoro-(C₁-C₆)-alkoxy, halo,

[0020] —OR⁹, cyano, —S(O)_(m)R¹⁰, —NR⁹R⁹, —SO₂NR⁹R⁹, —NR⁹COR¹⁰ or—NR⁹SO₂R¹⁰ and optionally benzo-fused, and said piperazin-1-yl andhomopiperazin-1-yl being optionally substituted on the ring nitrogenatom not attached to the C₂-C₆ alkylene group by C₁-C₆ alkyl, phenyl,C₁-C₆ alkoxy-(C₂-C₆)-alkyl, R⁹R⁹N—(C₂-C₆)-alkyl, fluoro-(C₁-C₆)-alkyl,C₂-C₅ alkanoyl, —COOR¹⁰, C₃-C₈ cycloalkyl, —SO₂R¹⁰,

[0021] —SO₂NR⁹R⁹ or —CONR⁹R⁹, or

[0022] (ii) —NR¹¹R¹²;

[0023] R⁹ is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl or phenyl;

[0024] R¹⁰ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl or phenyl;

[0025] R¹¹ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl or benzyl;

[0026] R¹² is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, benzyl,fluoro-(C₁-C₆)-alkyl, —CONR⁹R⁹, —COOR¹⁰, —COR¹⁰, —SO₂R¹⁰ or —SO₂NR⁹R⁹,said C₁-C₆ alkyl being optionally substituted by phenyl;

[0027] R¹³ is phenyl, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, eachbeing optionally substituted by C₁-C₆ alkyl, C₁-C₆ alkoxy, halo orcyano;

[0028] R¹⁴ is H or C₁-C₆ alkyl optionally substituted by cyclopropyl;

[0029] R¹⁵ is azetidin-3-yl, pyrrolidin-3-yl, piperidin-3-yl,piperidin-4-yl, homopiperidin-3-yl or homopiperidin-4-yl, each beingoptionally substituted by R¹³, C₁-C₆ alkyl, C₃-C₈ cycloalkyl or benzyl;

[0030] m is 0, 1 or 2;

[0031] X is —CH₂— or —CH₂CH₂—; and

[0032] Y is CO, CS, SO₂ or C═N(CN).

[0033] In the above definitions, halo means fluoro, chloro, bromo oriodo and alkyl, alkylene, alkarioyl and alkoxy groups containing therequisite number of carbon atoms can be unbranched or branched chain.Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, sec-butyl and t-butyl. Examples of alkoxy include methoxy,ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy andt-butoxy. Examples of alkanoyl include acetyl and propanoyl. Examples ofalkylene include methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene,1,2-propylene, 1,3-propylene and 2,2-propylene. Examples of cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl.

[0034] The pharmaceutically acceptable salts of the compounds of theformula (I) include the acid addition and the base salts thereof.

[0035] Suitable acid addition salts are formed from acids which formnon-toxic salts and examples are the hydrochloride, hydrobromide,hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogenphosphate, acetate, maleate, fumarate, lactate, tartrate, citrate,gluconate, succinate, saccharate, benzoate, methanesulphonate,ethanesulphonate, benzenesulphonate, para-toluenesulphonate and pamoatesalts.

[0036] Suitable base salts are formed from bases which form non-toxicsalts and examples are the sodium, potassium, aluminium, calcium,magnesium, zinc and diethanolamine salts.

[0037] For a review on suitable salts see Berge et al, J. Pharm. Sci.,66, 1-19, 1977.

[0038] The pharmaceutically acceptable solvates of the compounds of theformula (I) include the hydrates thereof.

[0039] Also included within the present scope of the compounds of theformula (I) are polymorphs thereof.

[0040] A compound of the formula (I) may contain one or more additionalasymmetric carbon atoms and therefore exist in two or morestereoisomeric forms. The present invention includes the individualstereoisomers of the compounds of the formula (I) together with, whereappropriate, the individual tautomers thereof, and mixtures thereof.

[0041] Separation of diastereoisomers may be achieved by conventionaltechniques, e.g. by fractional crystallisation, chromatography orH.P.L.C. of a stereoisomeric mixture of a compound of the formula (I) ora suitable salt or derivative thereof. An individual enantiomer of acompound of the formula (I) may also be prepared from a correspondingoptically pure intermediate or by resolution, such as by H.P.L.C. of thecorresponding racemate using a suitable chiral support or by fractionalcrystallisation of the diastereoisomeric salts formed by reaction of thecorresponding racemate with a suitable optically active acid or base, asappropriate.

[0042] Preferably, R¹ is C₁-C₆ alkyl optionally substituted by 1 or 2substituents each independently selected from phenyl, naphthyl andfluorenyl, said phenyl, naphthyl and fluorenyl being optionallysubstituted by C₁-C₆ alkyl, C₁-C₆ alkoxy, halo or cyano.

[0043] Preferably, R¹ is C₁-C₆ alkyl substituted by 1 or 2 substituentseach independently selected from phenyl, naphthyl and fluorenyl, saidphenyl, naphthyl and fluorenyl being optionally substituted by C₁-C₆alkyl, C₁-C₆ alkoxy, halo or cyano.

[0044] Preferably, R¹ is C₁-C₄ alkyl substituted by 1 or 2 substituentseach independently selected from phenyl, naphthyl and fluorenyl, saidphenyl, naphthyl and fluorenyl being optionally substituted by C₁-C₆alkyl, C₁-C₆ alkoxy, halo or cyano.

[0045] Preferably, R¹ is methyl or ethyl substituted by 1 or 2substituents each independently selected from phenyl, naphthyl andfluorenyl, said phenyl, naphthyl and fluorenyl being optionallysubstituted by C₁-C₆ alkyl, C₁-C₆ alkoxy, halo or cyano.

[0046] Preferably, R¹ is methyl or ethyl substituted by 1 or 2substituents each independently selected from phenyl, naphthyl andfluorenyl, said phenyl, naphthyl and fluorenyl being optionallysubstituted by C₁-C₆ alkyl or halo.

[0047] Preferably, R¹ is diphenylethyl, di(chlorophenyl)ethyl,di(methylphenyl)ethyl, naphthylmethyl or fluorenylmethyl.

[0048] Preferably, R¹ is 2,2-diphenyleth-1-yl,2,2-di(4-chlorophenyl)eth-1-yl, 2,2-di(3-chlorophenyl)eth-1-yl,2,2-di(4-methylphenyl)eth-1-yl, 2,2-di(3-methylphenyl)eth-1-yl,naphth-1-ylmethyl or fluoren-9-ylmethyl.

[0049] Preferably, R¹ is 2,2-diphenyleth-1-yl.

[0050] Preferably, R² is H or C₁-C₄ alkyl.

[0051] Preferably, R² is H or C₁-C₂ alkyl.

[0052] Preferably, R² is H or methyl.

[0053] Preferably, R² is H.

[0054] Preferably R³ and R⁴ do not form part of the same cyclicstructure.

[0055] Preferably, R³ is H or C₁-C₆ alkyl.

[0056] Preferably, R³ is H or C₁-C₄ alkyl.

[0057] Preferably, R³ is H or C₁-C₂ alkyl.

[0058] Preferably, R³ is H or methyl.

[0059] Preferably, R³ is H.

[0060] Preferably, R⁴ is (a) C₁-C₄ alkyl substituted by —R¹⁵, C₃-C₆cycloalkyl or —R¹⁵; or (b) —(C₂-C₄ alkylene)—R3, or (c) —(C₁-C₄alkylene)—R¹³.

[0061] Preferably, R⁴ is (a) C₁-C₂ alkyl substituted by —R¹⁵, C₅-C₆cycloalkyl or —R¹⁵; or (b) —(ethylene)—R⁸, or (c) —(C₁-C₂ alkylene)—R¹³.

[0062] Preferably, R⁴ is —CH₂R⁵, cyclohexyl, —R¹⁵, —CH₂CH₂R⁸, —CH₂R¹³ or—CH₂CH₂R¹³.

[0063] Preferably, R⁴ is 2-diisopropylaminoeth-1-yl or2-piperidin-1-yleth-1-yl.

[0064] Preferably, R⁵ is —CH₂OH or —CONH(C₁-C₆ alkyl).

[0065] Preferably, R⁵ is —CH₂OH or —CONH(C₁-C₄ alkyl).

[0066] Preferably, R⁵ is —CH₂OH or —CONH(C₁-C₂ alkyl).

[0067] Preferably, R⁵ is —CH₂OH or —CONHCH₂CH₃.

[0068] Preferably, R⁸ is (i) piperidin-1-yl, optionally substituted on aring carbon atom by C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, C₁-C₆alkoxy-(C₁-C₆)-alkyl, R⁹R⁹N—(C₁-C₆)-alkyl, fluoro-(C₁-C₆)-alkyl,—CONR⁹R⁹, —COOR⁹ or C₂-C₅ alkanoyl, optionally substituted on a ringcarbon atom not adjacent to a ring nitrogen atom byfluoro-(C₁-C₆)-alkoxy, halo, —OR⁹, cyano, —S(O)_(m)R¹⁰, —NR⁹R⁹,—SO₂NR⁹R⁹, —NR⁹COR¹⁰ or —NR⁹SO₂R¹⁰ and optionally benzo-fused, or (ii)—NR¹¹R¹².

[0069] Preferably, R⁸ is (i) piperidin-1-yl, optionally substituted on aring carbon atom by C₁-C₆ alkyl and optionally benzo-fused, or (ii)—NR¹¹R¹².

[0070] Preferably, R⁸ is (i) piperidin-1-yl, optionally substituted on aring carbon atom by C₁-C₃ alkyl and optionally benzo-fused, or (ii)—NR¹¹R¹².

[0071] Preferably, R⁸ is (i) piperidin-1-yl, optionally substituted on aring carbon atom by methyl or propyl and optionally benzo-fused, or (ii)—NR¹¹R¹².

[0072] Preferably, R⁸ is piperidin-1-yl, 4-(2-propyl)piperidin-1-yl,2,2,6,6-tetramethylpiperidin-1-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl or—NR¹¹R¹².

[0073] Preferably, R¹¹ is C₁-C₆ alkyl or C₃-C₈ cycloalkyl.

[0074] Preferably, R¹¹ is C₁-C₅ alkyl or C₃-C₆ cycloalkyl.

[0075] Preferably, R¹¹ is propyl, butyl, pentyl, cyclohexyl orcyclopentyl.

[0076] Preferably, R¹¹ is —CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH₂CH(CH₃)₂,—C(CH₃)₃, —CH(CH₂CH₃)₂, cyclohexyl or cyclopentyl.

[0077] Preferably, R¹² is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, —COR¹⁰ or—SO₂R¹⁰ said C₁-C₆ alkyl being optionally substituted by phenyl.

[0078] Preferably, R¹² is C₁-C₅ alkyl, C₃-C₆ cycloalkyl, —COR¹⁰ or—SO₂R¹⁰ said C₁-C₆ alkyl being optionally substituted by phenyl.

[0079] Preferably, R¹² is propyl, butyl, pentyl, cyclohexyl,cyclopentyl, phenylbutyl, —COPh or —SO₂Ph.

[0080] Preferably, R¹² is —CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH₂CH(CH₃)₂,—C(CH₃)₃, —CH(CH₂CH₃)₂, —C(CH₃)₂Ph, —SO₂Ph, —COPh, cyclohexyl orcyclopentyl.

[0081] Preferably, R¹³ is phenyl or pyridin-2-yl, each being optionallysubstituted by C₁-C₆ alkyl, C₁-C₆ alkoxy, halo or cyano.

[0082] Preferably, R¹³ is phenyl or pyridin-2-yl.

[0083] Preferably, R¹⁵ is pyrrolidin-3-yl or piperidin-4-yl, each beingoptionally substituted by R¹³, C₁-C₆ alkyl, C₃-C₈ cycloalkyl or benzyl.

[0084] Preferably, R¹⁵ is pyrrolidin-3-yl or piperidin-4-yl, each beingoptionally substituted by R¹³ or benzyl.

[0085] Preferably, R¹⁵ is 1-benzyl-piperidin-4-yl,(1-benzyl-piperidin-4-yl)methyl, 1-(2-pyridinyl)piperidin-4-yl, or1-benzyl-pyrrolidin-3-yl.

[0086] Preferably, X is —CH₂—.

[0087] Preferably, Y is CO or C═N(CN).

[0088] Preferably, Y is CO.

[0089] Preferred individual compounds of the formula (I) includeExamples 1-40 listed below and pharmaceutically acceptable salts andsolvates thereof.

[0090] All of the compounds of the formula (I) can be prepared byconventional routes such as by the procedures described in the generalmethods presented below or by the specific methods described in theExamples section, or by similar methods thereto. The present inventionalso encompasses any one or more of these processes for preparing thecompounds of formula (I), in addition to any novel intermediates usedtherein.

[0091] In the following general methods, R¹, R², R³, R⁴, R⁵, X and Y areas previously defined for a compound of the formula (I) unless otherwisestated. 1. Compounds of the formula (I) in which R⁵ is —CONR¹⁴R¹⁴ may beprepared by the deprotection of a compound of the formula

[0092] wherein P¹ and P² are suitable protecting groups which may be thesame or different and may optionally form part of the same protectinggroup. Compounds of the formula (I) in which R⁵ is —CH₂OH may beprepared by the deprotection of a compound of the formula

[0093] wherein P¹, P² and P³ are suitable protecting groups which may bethe same or different, P¹ and P² optionally forming part of the sameprotecting group. When deprotecting a compound of the formula (II) or acompound of the formula (III), the relevant protecting groups may beremoved separately, progressing through one or more semi-protectedintermediates, or together, or in any combination. Examples of suitableprotecting groups will be apparent to the skilled person [see, forinstance, ‘Protecting groups in Organic Synthesis (Second Edition)’,Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991].Preferred individual protecting groups are alkanoyl and aroyl. Preferredprotecting groups where P¹ and P² form part of the same protecting groupare where P¹ and P² taken together are C₁-C₆ alkylene. Particularlypreferred individual protecting groups are acetyl and benzoyl. Aparticularly preferred protecting group where P¹ and P² form part of thesame protecting group is where P¹ and P² taken together aredimethylmethylene. Suitable conditions for the deprotection are wellknown in the art [see, for instance, ‘Protecting groups in OrganicSynthesis (Second Edition)’, Theodora W. Green and Peter G. M. Wuts,John Wiley and Sons, 1991]. In a typical procedure, a solution of acompound of the formula (III), wherein P¹, P² and P³ are each acetyl, ina suitable solvent, such as methanol, is treated with a nucleophilicreagent, such as ammonia or a primary amine, or a base such as potassiumcarbonate, typically at room temperature. In another typical procedure,a solution of a compound of the formula (II), wherein P¹ and P² are eachbenzoyl, in a suitable solvent, such as methanol, is treated with anucleophilic reagent, such as ammonia or a primary amine, or a base suchas potassium carbonate, typically at a temperature from room temperatureto 60° C.

[0094] Compounds of the formula (II) in which X is —CH₂— (i.e. compoundsof the formula (IIA)) and compounds of the formula (III) in which X is—CH₂— (i.e. compounds of the formula (IIIA)) may be prepared accordingto the route shown in Scheme 1 wherein P⁴ represents a suitableprotecting group.

[0095] As shown in Scheme 1, compounds of the formula (IIA) may beprepared by the reaction of a compound of the formula

[0096] (in which P¹ and P² are as defined above) with trimethylsilyltrifluoromethanesulfonate and a compound of the formula (IV) which hasbeen derivatised with N,O-bis(trimethylsilyl)acetamide. In a typicalprocedure, the compound of the formula (IV) is heated in the presence ofa suitable solvent, such as 1,1,1-trichloroethane, withN,O-bis(trimethylsilyl)acetamide at an elevated temperature, preferablyat about 50° C. The mixture is then allowed to cool and the solvent isevaporated. A solution of the residue in a suitable solvent, such astoluene, is treated with the compound of the formula (V) andtrimethylsilyl trifluoromethanesulfonate and the mixture is heated,preferably under reflux, under a nitrogen atmosphere, to give thecompound of the formula (IIA).

[0097] Compounds of the formula (IIIA) may be prepared by the reactionof a compound of the formula

[0098] (in which P¹, P² and P³ are as defined above) with trimethylsilyltrifluoromethanesulfonate and a compound of the formula (IV) which hasbeen derivatised with N,O-bis(trimethylsilyl)acetamide. In a typicalprocedure, the compound of the formula (IV) is heated in the presence ofa suitable solvent, such as 1,1,1-trichloroethane, withN,O-bis(trimethylsilyl)acetamide at an elevated temperature, preferablyat 50° C. The mixture is then allowed to cool and the solvent isremoved. A solution of the residue in a suitable solvent such as tolueneis treated with the compound of the formula (VI) and trimethylsilyltrifluoromethanesulfonate and the mixture is heated, preferably underreflux, under a nitrogen atmosphere, to give the compound of the formula(IIIA).

[0099] Compounds of the formula (IV) may be prepared by the deprotectionof a compound of the formula (VII) wherein P⁴ is a suitable protectinggroup. Examples of suitable protecting groups will be apparent to theskilled person [see, for instance, ‘Protecting groups in OrganicSynthesis (Second Edition)’, Theodora W. Green and Peter G. M. Wuts,John Wiley and Sons, 1991]. A preferred protecting group istetrahydropyran-2-yl. Suitable conditions for the deprotection are wellknown in the art [see, for instance, ‘Protecting groups in OrganicSynthesis (Second Edition)’, Theodora W. Green and Peter G. M. Wuts,John Wiley and Sons, 1991]. In a typical procedure, where P⁴ istetrahydropyran-2-yl, the protecting group is removed by treating asolution of the compound of the formula (VII) in a suitable solvent,such as methanol, with an acid such as hydrochloric acid, preferably 2Maqueous hydrochloric acid.

[0100] Compounds of the formula (VII) in which Y is CO may be preparedby the reaction of a compound of the formula

[0101] in which L¹ is a suitable leaving group, with a compound of theformula (VIII) in a suitable solvent, such as a mixture of toluene andisopropanol, typically at an elevated temperature, preferably underreflux. The leaving group L¹ is preferably halo (e.g. chloro) orimidazol-1-yl, most preferably imidazol-1-yl. Compounds of the formula(X) wherein L¹ is imidazol-1-yl may be prepared by the reaction of acompound of the formula

R³R⁴NH  (XI)

[0102] with 1,1′-carbonyldiimidazole. In a typical reaction a compoundof the formula (XI) is added to a solution of 1,1′-carbonyldiimidazolein a suitable solvent such as dichloromethane. Compounds of the formula(XI) are either commercially available or may be prepared by standardtechniques well known to persons skilled in the art. Other compounds ofthe formula (X) are either commercially available or easily prepared bymethods well known to the person skilled in the art.

[0103] Compounds of the formula (VII) in which Y is CO may also beprepared by the reaction of a compound of the formula (VII) with acompound of the formula

L²COL³  (XII)

[0104] in which L² and L³ are suitable leaving groups, to form anintermediate of the formula

[0105] in which L⁴ represents either of the leaving groups L² or L³ andP⁴ is as defined above, followed by the addition of a compound of theformula (XI) to the reaction mixture. Preferably, L² and L³ are eachhalo or imidazol-1-yl. Most preferably, L² and L³ are eachimidazol-1-yl. In a typical example, where L² and L³ are eachimidazol-1-yl, a solution of the compound of the formula (VIII) in asuitable solvent, such as dichloromethane, is treated with1,1′-carbonyldiimidazole. The reaction mixture is stirred, preferably atroom temperature, until thin layer chromatography (TLC) indicates asubstantially complete reaction has occurred and then a compound of theformula (XI) is added to give the compound of the formula (VII).

[0106] Compounds of the formula (VII) in which Y is CS may be preparedby the reaction of a compound of the formula

L⁵L⁶C═S  (XIV)

[0107] in which L⁵ and L⁶ are suitable leaving groups, with a compoundof the formula (VIII), to form an intermediate of the formula

[0108] in which L⁷ represents either of the leaving groups L⁵ or L⁶,followed by the addition of a compound of the formula (XI). The leavinggroups L⁵ and L⁶ may be the same or different and are typically selectedfrom —S(C₁-C₆ alkyl) or imidazol-1-yl. Preferably, L⁵ and L⁶ are eachmethylthio or imidazol-1-yl. In a typical procedure, a solution of thecompound of the formula (XIV) in a suitable solvent, such as ethanol, istreated with the compound of the formula (VII), preferably at anelevated temperature, most preferably under reflux. When analysis bythin layer chromatography shows that a substantially complete reactionhas occurred, a compound of the formula (XI) is added and the reactionmixture is preferably heated, most preferably under refluxAlternatively, compounds of the formula (VII) in which Y is CS may beprepared by the reaction of a compound of the formula (XIV) in which L⁵and L⁶ are as defined above, with a compound of the formula (XI), toform an intermediate of the formula

[0109] in which L⁸ represents either of the leaving groups L⁵ or L⁶,followed by the addition of a compound of the formula (VIII). In atypical procedure, a solution of the compound of the formula (XIV) in asuitable solvent, such as ethanol, is treated with the compound of theformula (XI), preferably at an elevated temperature, most preferablyunder reflux. When analysis by thin layer chromatography shows that asubstantially complete reaction has occurred, a compound of the formula(VII) is added and the reaction mixture is preferably heated, mostpreferably under reflux.

[0110] Compounds of the formula (VII) in which Y is SO₂ may be preparedby the reaction of a compound of the formula

R³R⁴NSO₂L⁹  (XVII)

[0111] in which L⁹ is a suitable leaving group, typically halo, with acompound of the formula (VIII), optionally in the presence of an acidacceptor. Preferably, L⁹ is chloro. In a typical example, a solution ofthe compound of the formula (VII) in a suitable solvent, such aspyridine, is treated with the compound of the formula (XVII) andpreferably heated, most preferably at 90° C. Compounds of the formula(XVII) may be prepared by treating a compound of the formula

R³R⁴NSO₃H (XVIII)

[0112] with an activating agent. In a typical example, where L⁹ ischloro, a solution of a compound of the formula (XVIII), in a suitablesolvent such as toluene, is treated with PCl₅ and heated, preferablyunder reflux. Compounds of the formula (XVIII) may be prepared bytreating a compound of the formula (XI) with chlorosulphonic acid. In atypical procedure, a solution of the compound of the formula (XI) in asuitable solvent, such as dichloromethane, is treated withchlorosulphonic acid, optionally in the presence of a proton acceptorsuch as triethylamine.

[0113] Compounds of the formula (VII) in which Y is C═N(CN) may beprepared by the reaction of a compound of the formula

L¹⁰L¹¹C═N(CN)  (XIX)

[0114] in which L¹⁰ and L¹¹ are suitable leaving groups, with a compoundof the formula (VIII), to form an intermediate of the formula

[0115] in which L¹² represents either of leaving groups L¹⁰ or L¹¹,followed by the addition of a compound of the formula (XI). The leavinggroups L¹⁰ and L¹¹ may be the same or different and are typicallyselected from halo and —S(C₁-C₆ alkyl). Preferably, L¹⁰ and L¹¹ are eachmethythio. In a typical procedure, where L¹⁰ and L¹¹ are eachmethylthio, a solution of a compound of the formula (VII) in a suitablesolvent, such as ethanol, is treated withdimethylcyanothioimidocarbamate, preferably at room temperature. When asubstantially complete reaction is indicated by thin layerchromatography (TLC), a compound of the formula (XI) is added and thereaction mixture is preferably heated, most preferably under reflux.

[0116] Alternatively, compounds of the formula (VII) in which Y isC═N(CN) may be prepared by the reaction of a compound of the formula(XIX) in which L¹⁰ and L¹¹ are as defined above, with a compound of theformula (XI), to form an intermediate of the formula

[0117] in which L¹³ represents either of the leaving groups L¹⁰ or L¹¹,followed by the addition of a compound of the formula (VII). In atypical procedure, where L¹¹ and L¹¹ are each methylthio, a solution ofa compound of the formula (XI) in a suitable solvent, such as ethanol,is treated with dimethylcyanothioimidocarbamate, preferably at roomtemperature. When a substantially complete reaction is indicated by thinlayer chromatography (TLC), a compound of the formula (VII) is added andthe reaction mixture is preferably heated, most preferably under reflux.

[0118] Compounds of the formula (VII) may be prepared by the reductionof a compound of the formula (IX) with a suitable reducing agent,preferably a palladium catalyst and hydrogen gas, in the presence of acompound of the formula

R²NH₂  (XXIA).

[0119] In a typical procedure, where R²═H, a compound of the formula(IX) is dissolved in a suitable solvent, such as ethanol, which has beensaturated with ammonia gas, a palladium catalyst such as 10% w/wpalladium on carbon is added and the reaction mixture is stirred underan atmosphere of hydrogen gas, typically at a pressure of 414 kPa (60psi). Compounds of the formula (IX) are known in the art (see, forexample, WO-A-00/23457). Compounds of the formula (XXIA) are eithercommercially available or readily prepared by methods well known tothose skilled in the art.

[0120] Compounds of the formula (III) in which X is —CH₂CH₂— (i.e.compounds of the formula (IIIB)) may be prepared according to the routeshown in Scheme 2 wherein A represents an activating group and P¹, P²and P³ represent suitable protecting groups. P¹, P² and P³ may be thesame or different, P¹ and P² optionally forming part of the sameprotecting group. Examples of suitable protecting groups will beapparent to the skilled person [see, for instance, ‘Protecting groups inOrganic Synthesis (Second Edition)’, Theodora W. Green and Peter G. M.Wuts, John Wiley and Sons, 1991]. Preferred individual protecting groupsare tri(C₁-C₆)alkylsilyl, di(C₁-C₆)alkylphenylsilyl and(C₁-C₆)alkyldiphenylsilyl. Preferred protecting groups where P¹ and P²form part of the same protecting group are where P¹ and P² takentogether are C₁-C₆ alkylene. Particularly preferred individualprotecting groups are tert-butyidimethylsilyl and triethylsilyl. Aparticularly preferred protecting group where P¹ and P² form part of thesame protecting group is where P¹ and P² taken together aredimethylmethylene.

[0121] In Scheme 2, the compounds of the formula (IIIB) in which Y is COmay be prepared by the reaction of compound of the formula (X), in whichL¹ is as defined above, with a compound of the formula (XXII) in asuitable solvent, such as a mixture of toluene and isopropanol,typically at an elevated temperature, preferably under reflux.

[0122] Alternatively, compounds of the formula (IIIB) in which Y is COmay be 10 prepared by the reaction of a compound of the formula (XXII)with a compound of the formula (XII), in which L² and L³ are as definedabove, to form an intermediate of the formula

[0123] in which L¹⁴ represents either of leaving groups L² or L³. Theintermediate (XXVII) is reacted with a compound of the formula (XI) toprovide a compound of the formula (IIIB). In a typical example, where L²and L³ are each imidazol-1-yl, a solution of the compound of the formula(XXII) in a suitable solvent, such as dichloromethane, is treated with1,1′-carbonyldiimidazole. The reaction mixture is stirred, preferably atroom temperature, until thin layer chromatography (TLC) indicates asubstantially complete reaction has occurred and then a compound of theformula (XI) is added to give the compound of the formula (IIIB).

[0124] Compounds of the formula (I) in which Y is CS may be prepared bythe reaction of a compound of the formula (XIV) in which L⁵ and L⁶ areas defined above, with a compound of the formula (XXII), to form anintermediate of the formula

[0125] in which L¹⁵ represents either of leaving groups L⁵ or L⁶. Theintermediate of the formula (XXVIII) is reacted with a compound of theformula (XI) to provide a compound of the formula (IIIB). In a typicalprocedure, a solution of the compound of the formula (XIV) in a suitablesolvent, such as ethanol, is treated with the compound of the formula(XXII), preferably at an elevated temperature, most preferably underreflux. When analysis by thin layer chromatography shows that asubstantially complete reaction has occurred, the compound of theformula (XI) is added and the reaction mixture is preferably heated,most preferably under reflux.

[0126] Alternatively, compounds of the formula (IIIB) in which Y is CSmay be prepared by the reaction of a compound of the formula (XVI), inwhich L⁸ is as defined above, with a compound of the formula (XXII). Ina typical procedure, a solution of the compound of the formula (XVI) ina suitable solvent, such as ethanol, is treated with the compound of theformula (XXII) and preferably heated, most preferably under reflux.

[0127] Compounds of the formula (IIIB) in which Y is SO₂ may be preparedby the reaction of a compound of the formula (XVII), in which L⁹ is asdefined above, with a compound of formula (XXII), optionally in thepresence of an acid acceptor. In a typical procedure, a solution of thecompound of the formula (XVII) in a suitable solvent, such as pyridine,is treated with the compound of the formula (XXII) and heated, typicallyat 90° C.

[0128] Compounds of the formula (IIIB) in which Y is C═N(CN) may beprepared by the reaction of a compound of the formula (XIX) in which L¹⁰and L¹¹ are as defined above, with a compound of the formula (XXII), toform an intermediate of the formula

[0129] in which L¹⁶ represents either of leaving groups L¹⁰ or L¹¹. Theintermediate of the formula (XXIX) is reacted with a compound of theformula (XI) to provide a compound of the formula (IIIB). In a typicalprocedure, where L¹⁰ and L¹¹ are each me thylthio, a solution of acompound of the formula (XXII) in a suitable solvent, such as ethanol,is treated with dimethylcyanothioimidocarbamate, preferably at roomtemperature. When a substantially complete reaction is indicated by thinlayer chromatography (TLC), a compound of the formula (XI) is added andthe reaction mixture is preferably heated, most preferably under reflux.

[0130] Alternatively, compounds of the formula (IIIB) in which Y isC═N(CN) may be prepared by the reaction of a compound of the formula(XXI), in which L¹³ is as defined above, with a compound of the formula(XXII). In a typical procedure, a solution of the compound of theformula (XXI) in a suitable solvent, such as ethanol, is treated withthe compound of the formula (XXII) and preferably heated, mostpreferably under reflux.

[0131] Compounds of the formula (XXII) may be prepared by the reductionof a compound of the formula (XXIII) with a suitable reducing agent inthe presence of a compound of the formula (XXIA). A preferred reducingagent is Raney nickel, optionally in the presence of hydrogen gas. In atypical procedure, where R² H, the compound of the formula (XXIII) isdissolved in a suitable solvent, such as ethanol, which has beensaturated with ammonia gas, Raney nickel is added and the reactionmixture is shaken, preferably at room temperature.

[0132] Compounds of the formula (XXIII) may be prepared by thedisplacement of a leaving group ‘OA’, in which A is an activating group,from a compound of the formula (XXIV) with cyanide anion. In a typicalexample, a solution of the compound of the formula (XXIV) in a suitablesolvent, such as N,N-dimethylformamide, is treated with a source ofcyanide ion, such as potassium cyanide to give the compound of theformula (XXIII). Examples of suitable choices for A will be apparent tothe skilled man [see for example ‘Advanced Organic Chemistry (ThirdEdition)’, Jerry March, Wiley-Interscience, 1985]. Preferably, A is(C₁-C₆)alkylsulphonyl, phenylsulphonyl or ((C₁-C₆)alkylphenyl)sulphonyl.Most preferably, A is methylsulphonyl.

[0133] Compounds of the formula (XXIV) may be prepared by the activationof the free hydroxyl in a compound of the formula (XXV). In a typicalexample, where A is methylsulphonyl, a solution of the compound of theformula (XXV) in a suitable solvent, such as dichloromethane, is treatedwith methanesulfonyl chloride in the presence of a proton acceptor suchas triethylamine.

[0134] Compounds of the formula (XXV) may be prepared by the reductionof an ester of the formula (XXVI) with a suitable reducing agent, suchas lithium borohydride, in a suitable solvent, such as tetrahydrofuran.

[0135] Compounds of the formula (II) in which X is —CH₂CH₂— (i.e.compounds of the formula (IIB)) may be prepared according to the routeshown in Scheme 3 wherein A represents an activating group, as definedabove, and P¹ and P² represent suitable protecting groups. P¹ and P² maybe the same or different and optionally form part of the same protectinggroup. Examples of suitable protecting groups will be apparent to theskilled person [see, for instance, ‘Protecting groups in OrganicSynthesis (Second Edition)’, Theodora W. Green and Peter G. M. Wuts,John Wiley and Sons, 1991]. Preferred individual protecting groups aretri(C₁-C₆)alkylsilyl, di(C₁-C₆)alkylphenylsilyl and(C₁-C₆)alkyldiphenylsilyl. Preferred protecting groups where P¹ and P²form part of the same protecting group are where P¹ and P² takentogether are C₁-C₆ alkylene. Particularly preferred individualprotecting groups are tert-butyidimethylsilyl and triethylsilyl. Aparticularly preferred protecting group where P¹ and P² form part of thesame protecting group is where P¹ and P² taken together aredimethylmethylene.

[0136] In Scheme 3, the compounds of the formula (IIB) in which Y is COmay be prepared by the reaction of a compound of the formula (X), inwhich L¹ is as defined above, with a compound of the formula (XXX) in asuitable solvent, such as a mixture of toluene and isopropanol,typically at an elevated temperature, preferably under reflux.

[0137] Alternatively, compounds of the formula (IIB) in which Y is COmay be prepared by the reaction of a compound of the formula (XXX) witha compound of the formula (XII), in which L² and L³ are as definedabove, to form an intermediate of the formula

[0138] in which L¹⁷ represents either of leaving groups L² or L³. Theintermediate of the formula (XXXV) is reacted with a compound of theformula (XI) to form a compound of the formula (IIB). In a typicalexample, a solution of the compound of the formula (XXX) in a suitablesolvent, such as dichloromethane, is treated with the compound of theformula (XII). The reaction mixture is stirred, preferably at roomtemperature, until thin layer chromatography (TLC) indicates asubstantially complete reaction has occurred and then a compound of theformula (XI) is added to give the compound of the formula (IIB).

[0139] Compounds of the formula (IIB) in which Y is CS may be preparedby the reaction of a compound of the formula (XIV) in which L⁵ and L⁶are as defined above, with a compound of the formula (XXX), to form anintermediate of the formula

[0140] in which L¹⁸ represents either of leaving groups L⁵ or L⁶. Theintermediate of the formula (XXXVI) is reacted with a compound of theformula (XI) to provide a compound of the formula (IIB). In a typicalprocedure, a solution of the compound of the formula (XIV) in a suitablesolvent, such as ethanol, is treated with the compound of the formula(XXX), typically at an elevated temperature. Preferably, the reactionmixture is heated under reflux. When analysis by thin layerchromatography shows that a substantially complete reaction hasoccurred, the compound of the formula (XI) is added and the reactionmixture is preferably heated, most preferably under reflux.

[0141] Alternatively, compounds of the formula (IIB) in which Y is CSmay be prepared by the reaction of a compound of the formula (XVI), inwhich L⁸ is as defined above, with a compound of the formula (XXX). In atypical procedure, a solution of the compound of the formula (XVI) in asuitable solvent, such as ethanol, is treated with the compound of theformula (XXX), typically at an elevated temperature. Preferably, thereaction mixture is heated under reflux.

[0142] Compounds of the formula (IIB) in which Y is SO₂ may be preparedby the reaction of a compound of the formula (XVII) in which L⁹ is asdefined above with a compound of the formula (XXX). In a typicalexample, a solution of the compound of the formula (XXX) in a suitablesolvent, such as pyridine, is treated with the compound of the formula(XVII) and heated, typically at 90° C.

[0143] Compounds of the formula (IIB) in which Y is C═N(CN) may beprepared by the reaction of a compound of the formula (XIX) in which L¹⁰and L¹¹ are as defined above, with a compound of the formula (XXX), toform an intermediate of the formula

[0144] in which L¹⁹ represents either of leaving groups L¹⁰ or L¹¹. Theintermediate of the formula (XXXVII) is reacted with a compound of theformula (XI) to provide a compound of the formula (IIB). In a typicalprocedure, where L¹⁰ and L¹¹ are each methylthio, a solution of acompound of the formula (XXX) in a suitable solvent, such as ethanol, istreated with dimethylcyanothioimidocarbamate, preferably at roomtemperature. When a substantially complete reaction is indicated by thinlayer chromatography (TLC), a compound of the formula (XI) is added andthe reaction mixture is preferably heated, most preferably under reflux.

[0145] Alternatively, compounds of the formula (IIB) in which Y isC═N(CN) may be prepared by the reaction of a compound of the formula(XXI), in which L¹³ is as defined above, with a compound of the formula(XXX). In a typical procedure, a solution of the compound of the formula(XXI) in a suitable solvent, such as ethanol, is treated with thecompound of the formula (XXX) and preferably heated, most preferablyunder reflux.

[0146] Compounds of the formula (XXX) may be prepared by the reductionof a compound of the formula (XXXI) with a suitable reducing agent inthe presence of a compound of the formula (XXIA). A preferred reducingagent is Raney nickel, optionally in the presence of hydrogen gas. In atypical example, where R² ═H, a compound of the formula (XXXI) isdissolved in a suitable solvent, such as ethanol, which has beensaturated with ammonia gas, Raney nickel is added and the reactionmixture is shaken, preferably at room temperature.

[0147] Compounds of the formula (XXXI) may be prepared by thedisplacement of a leaving group ‘OA’, from a compound of the formula(XXXII) with cyanide anion. In a typical example, a solution of thecompound of the formula (XXXII) in a suitable solvent, such asN,N-dimethylformamide, is treated with a source of cyanide ion, such aspotassium cyanide, to give the compound of the formula (XXXI).

[0148] Compounds of the formula (XXXII) may be prepared by theactivation of the free hydroxyl in a compound of the formula (XXXIII).In a typical example, where A is methylsulphonyl, a solution of thecompound of the formula (XXXIII) in a suitable solvent, such asdichloromethane, is treated with methanesulphonyl chloride in thepresence of a proton acceptor such as triethylamine.

[0149] Compounds of the formula (XXXIII) may be prepared by thereduction of an ester of the formula (XXXIV) with a suitable reducingagent, such as lithium borohydride, in a suitable solvent, such astetrahydrofuran.

[0150] 2. Compounds of the formula (I) may also be prepared by thederivatisation of a compound of the formula as described below.

[0151] Compounds of the formula (I) in which Y is CO may be prepared bythe reaction of a compound of the formula (X), in which L¹ is as definedabove, with a compound of the formula (XXXVIII) in a suitable solvent,such as a mixture of toluene and isopropanol, preferably at an elevatedtemperature, most preferably under reflux.

[0152] Alternatively, compounds of the formula (I) in which Y is CO maybe prepared by the reaction of a compound of the formula (XXXVIII) witha compound of the formula (XII), in which L² and L³ are as definedabove, to form an intermediate of the formula

[0153] in which L²⁰ represents either of leaving groups L² or L³. Theintermediate (XXXIX) is reacted with a compound of the formula (XI) toprovide a compound of the formula (I). In a typical example, where L²and L³ are each imidazol-1-yl, a solution of the compound of the formula(XXXVIII) in a suitable solvent, such as dichloromethane, is treatedwith 1,1′-carbonyldiimidazole. The reaction mixture is stirred,preferably at room temperature, until thin layer chromatography (TLC)indicates a substantially complete reaction has occurred and then acompound of the formula (XI) is added to give the compound of theformula (I).

[0154] Compounds of the formula (I) in which Y is CS may be prepared bythe reaction of a compound of the formula (XIV) in which L⁵ and L⁶ areas defined above, with a compound of the formula (XXXVIII), to form anintermediate of the formula

[0155] in which L²¹ represents either of the leaving groups L⁵ or L⁶.The intermediate of the formula (XXXX) is reacted with a compound of theformula (XI) to provide a compound of the formula (I). In a typicalprocedure, a solution of the compound of the formula (XXXVIII) in asuitable solvent, such as ethanol, is treated with the compound of theformula (XIV), preferably at an elevated temperature, most preferablyunder reflux. When analysis by thin layer chromatography shows that asubstantially complete reaction has occurred, a compound of the formula(XI) is added and the reaction mixture is preferably heated, mostpreferably under reflux.

[0156] Alternatively, compound of the formula (I) in which Y is CS maybe prepared by the reaction of a compound of the formula (XVI) in whichL⁸ is as defined above with a compound of the formula (XXXVIII). In atypical procedure, a solution of the compound of the formula (XVI) in asuitable solvent, such as ethanol, is treated with the compound of theformula (XXXVIII) and preferably heated, most preferably under reflux.

[0157] Compounds of the formula (I) in which Y is SO₂ may be prepared bythe reaction of a compound of the formula (XVII), in which L⁹ is asdefined above, with a compound of the formula (XXXVIII), optionally inthe presence of an acid acceptor. In a typical procedure, a solution ofthe compound of the formula (XXXVIII) in a suitable solvent, such aspyridine, is treated with the compound of the formula (XVII) and heated,typically at 90° C.

[0158] Compounds of the formula (I) in which Y is C═N(CN) may beprepared by the reaction of a compound of the formula (XIX) in which L¹⁰and L¹¹ are as defined above, with a compound of the formula (XXXVIII),to form an intermediate of the formula

[0159] in which L²² represents either of L¹⁰ or L¹¹. The intermediate ofthe formula (XXXXI) is reacted with a compound of the formula (XI) togive a compound of the formula (I). In a typical procedure, where L¹⁰and L¹¹ are each methylthio, a solution of a compound of the formula(XXXVIII) in a suitable solvent, such as ethanol, is treated withdimethylcyanothioimidocarbamate, preferably at room temperature. When asubstantially complete reaction is indicated by thin layerchromatography (TLC), a compound of the formula (XI) is added and thereaction mixture is preferably heated, most preferably under reflux, togive the compound of the formula (I).

[0160] Alternatively, compounds of the formula (I) in which Y is C═N(CN)may be prepared by the reaction of a compound of the formula (XXI), inwhich L¹³ is as defined above, with a compound of the formula (XXXVIII).In a typical procedure, a solution of the compound of the formula (XXI)in a suitable solvent, such as ethanol, is treated with the compound ofthe formula (XXXVIII) and preferably heated, most preferably underreflux.

[0161] Compounds of the formula (XXXVIII) may be prepared according tothe route shown in Scheme 4, wherein P¹, P² and P³ are as defined above.

[0162] Compounds of the formula (XXXVIII) in which R⁵ is —CH₂OH and X is—CH₂— may be prepared by reducing a compound of the formula (XXXXII) inthe presence of a compound of the formula (XXIA) to give a compound ofthe formula

[0163] in which P¹, P² and P³ are as defined above, and deprotecting thecompound of the formula (XXXXV). Alternatively, if the protecting groupsemployed are readily removed by the conditions chosen for the reduction,then the reducing and deprotecting steps will usually be performedtogether to give a compound of the formula (XXXVIII) directly from acompound of the formula (XXXXII). The reduction is carried out using asuitable reducing agent, such as a palladium catalyst and hydrogen gas,in the presence of a compound of formula (XXIA). Suitable conditions forthe deprotection are well known in the art [see, for instance,‘Protecting groups in Organic Synthesis (Second Edition)’, Theodora W.Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. In a typicalprocedure, where R² is H, P¹, P² and P³ are each acetyl and the reducingand deprotecting steps are carried out together, a compound of theformula (XXXXII) is dissolved in a suitable solvent, such as ethanol,which has been saturated with ammonia gas, a palladium catalyst, such as10% w/w palladium on carbon, is added and the reaction is stirred underan atmosphere of hydrogen gas, typically at a pressure of 414 kPa (60psi).

[0164] Compounds of the formula (XXXVIII) in which R⁵ is —CONR¹⁴R¹⁴ andX is —CH₂— may be prepared by reducing a compound of the formula(XXXXIII) in the presence of a compound of the formula (XXIA) to give acompound of the formula

[0165] wherein P¹ and P² are as defined above and deprotecting thecompound of the formula (XXXXVI). Alternatively, if the protectinggroups employed are readily removed by the conditions chosen for thereduction, then the reducing and deprotecting steps will usually beperformed together to give a compound of the formula (XXXVIII) directlyfrom a compound of the formula (XXXXIII). The reduction is carried outusing a suitable reducing agent, such as a palladium catalyst andhydrogen gas, in the presence of a compound of formula (XXIA). Suitableconditions for the deprotection are well known in the art [see, forinstance, ‘Protecting groups in Organic Synthesis (Second Edition)’,Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. In atypical procedure, where R² is H, P¹ and P² are each benzoyl and thereducing and deprotecting are carried out together, a compound of theformula (XXXXIII) is dissolved in a suitable solvent, such as ethanol,which has been saturated with ammonia gas, a palladium catalyst, such as10% w/w palladium on carbon, is added and the reaction is stirred underan atmosphere of hydrogen gas, typically at a pressure of 414 kPa (60psi).

[0166] Compounds of the formula (XXXXII) may be prepared by the reactionof an acetate of the formula (VI) with trimethylsilyltrifluoromethanesulfonate and a compound of the formula (XXXXIV) whichhas been derivatised with N,O-bis(trimethylsilyl)acetamide. In a typicalprocedure, a compound of the formula (XXXXIV) is heated, in the presenceof a suitable solvent, such as 1,1,1-trichloroethane, withN,O-bis(trimethylsilyl)acetamide, preferably under reflux. The mixtureis then allowed to cool and the solvent is removed. A solution of theresidue in a suitable solvent, such as toluene, is treated with theacetate of the formula (VI) and trimethylsilyltrifluoromethanesulfonate. The mixture so formed is preferably heated,most preferably under reflux, under a nitrogen atmosphere, to give thecompound of the formula (XXXXII).

[0167] Compounds of the formula (XXXXIII) may be prepared by thereaction of an acetate of the formula (V) with a compound of the formula(XXXXIV) and iodine. In a typical example, a compound of the formula(XXXXIV), a compound of the formula (V) and iodine are heated together,preferably at 150° C., under reduced pressure, preferably at 7 kPa (1psi).

[0168] Compounds of the formula (XXXXIV) are known in the art (see, forexample, WO-A-00/23457).

[0169] Compounds of the formula (XXXVIII) in which R⁵ is —CH₂OH and X is—CH₂CH₂— may be prepared by the deprotection of a compound of theformula (XXII), in which protecting groups P¹, P² and P³ are as definedabove. Suitable conditions for the deprotection are well known in theart [see, for instance, ‘Protecting groups in Organic Synthesis (SecondEdition)’, Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons,1991]. In a typical procedure, a solution of a compound of the formula(XXII), wherein P¹, P² and P³ are each tert-butyldimethylsilyl, in asuitable solvent, such as methanol, is treated with an acid such ashydrochloric acid, typically at room temperature.

[0170] Compounds of the formula (XXXVIII) in which R⁵ is —CONR¹⁴R¹⁴ andX is —CH₂CH₂— may be prepared by the deprotection of a compound of theformula (XXX) in which protecting groups P¹ and P² are as defined above.Suitable conditions for the deprotection are well known in the art [see,for instance, ‘Protecting groups in Organic Synthesis (Second Edition)’,Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. In atypical procedure, a solution of a compound of the formula (XXX),wherein P¹ and P² are each tert-butyidimethylsilyl, in a suitablesolvent, such as methanol, is treated with an acid such as hydrochloricacid, typically at room temperature.

[0171] Scheme 5, wherein P¹, P², P³ and P⁴ are as defined above,illustrates the preparation of compounds of the formula (XXVI) andcompounds of the formula (XXXIV) used in Schemes 2 and 3 respectively.

[0172] In Scheme 5, compounds of the formula (XXVI) may be prepared bythe reaction of a compound of the formula (V) with trimethylsilyltrifluoromethanesulfonate and a compound of the formula (XXXXVII) whichhas been derivatised with N,O-bis(trimethylsilyl)acetamide. In a typicalprocedure, the compound of the formula (XXXXVII) is heated in thepresence of a suitable solvent, such as 1,1,1-trichloroethane, withN,O-bis(trimethylsilyl)acetamide at an elevated temperature, preferablyunder reflux. The mixture is then allowed to cool and the solvent isremoved. A solution of the residue in a suitable solvent, such astoluene, is treated with the compound of the formula (V) andtrimethylsilyl trifluoromethanesulfonate and the mixture is heated,preferably under reflux, under a nitrogen atmosphere, to give thecompound of the formula (XXVI).

[0173] Compounds of the formula (XXXIV) may be prepared by the reactionof a compound of the formula (VI) with trimethylsilyltrifluoromethanesulfonate and a compound of the formula (XXXXVII) whichhas been derivatised with N,O-bis(trimethylsilyl)acetamide. In a typicalprocedure, the compound of the formula (XXXXVII) is heated in thepresence of a suitable solvent, such as 1,1,1-trichloroethane, withN,O-bis(trimethylsilyl)acetamide at an elevated temperature, preferablyunder reflux. The mixture is then allowed to cool and the solvent isremoved. A solution of the residue in a suitable solvent, such astoluene, is treated with the compound of the formula (VI) andtrimethylsilyl trifluoromethanesulfonate and the mixture is heated,preferably under reflux, under a nitrogen atmosphere, to give thecompound of the formula (XXXIV).

[0174] It may be desirable in certain cases, having regard to theconditions used in future steps, to change the protecting groups incompounds of the formula (XXVI) or (XXXIV) prepared in this way.Suitable conditions for both the deprotecting step are well known to theskilled person [see, for instance, ‘Protecting groups in OrganicSynthesis (Second Edition)’, Theodora W. Green and Peter G. M. Wuts,John Wiley and Sons, 1991]. In a typical procedure, where P¹, P² and,where appropriate, P³ are each acetyl, a solution of the compound of theformula (XXVI) or the compound of the formula (XXXIV), as the case maybe, in a suitable solvent, such as methanol, is treated with anucleophile such as ammonia or a primary amine, or a base such aspotassium carbonate, typically at room temperature. Suitable conditionsfor the subsequent protecting step are also well known to the skilledperson [see, for instance, ‘Protecting groups in Organic Synthesis(Second Edition)’, Theodora W. Green and Peter G. M. Wuts, John Wileyand Sons, 1991]. In a typical example, where the new protecting groupsare to be each tert-butyldimethylsilyl, a solution of the deprotectedintermediate, in a suitable solvent such as N,N-dimethylformamide, istreated with tert-butyldimethylsilylchloride and a suitable protonacceptor such as imidazole.

[0175] Compounds of the formula (XXXXVII) may be prepared by thedeprotection of a compound of the formula (XXXVIII). Suitable conditionsfor the deprotection are well known in the art [see, for instance,‘Protecting groups in Organic Synthesis (Second Edition)’, Theodora W.Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. In a typicalprocedure, where P⁴ is tetrahydropyran-2-yl, the protecting group may beremoved by treating a solution of the compound of the formula (XXXXVIII)in a suitable solvent, such as ethanol, with an acid such ashydrochloric acid.

[0176] Compounds of the formula (XXXXVIII) may be prepared by themethanolysis of a compound of the formula (IX). In a typical procedure,a solution of a compound of the formula (IX) in methanol is treated withan alkali metal methoxide, preferably sodium methoxide, and heated underreflux. The resulting mixture is cooled, evaporated, dissolved in asuitable solvent such as tetrahydrofuran and treated with an acid, suchas hydrochloric acid, preferably 2N hydrochloric acid, to give thecompound of the formula (XXXXVIII).

[0177] Compounds of the formula (V), as used in Schemes 1, 4 and 5, maybe prepared as shown in Scheme 6, wherein P¹ and P² are as definedabove.

[0178] In Scheme 6, compounds of the formula (V) may be prepared by thetreatment of a compound of the formula (XXXXIX) with a mixture of aceticacid, acetic anhydride and a strong acid such as hydrochloric orsulphuric acid with cooling (typically to −10° C.). A compound offormula (XXXXIX) may be prepared from an acid of the formula (XXXXX) byactivation of the acid as, for example, an acid chloride and treatmentof this activated intermediate with a compound of the formula

R¹⁴R¹⁴NH  (XXXXXI).

[0179] In a typical procedure, a compound of formula (XXXXX) isdissolved in a suitable inert solvent (e.g. dichloromethane) and treatedwith oxalyl chloride and a catalytic amount of N,N-dimethylformamide.After removal of excess solvent and reagent by evaporation under reducedpressure, the residue is dissolved in anhydrous dichloromethane andtreated with a compound of the formula (XXXXXI). With regard to theconditions employed in later steps, it may be appropriate to change theprotecting groups P¹ and P² in compounds of the formula (XXXXIX).Alternative, suitable protecting groups are well-known to the skilledperson [e.g. ‘Protecting Groups in Organic Synthesis (Second Edition)’,Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. In atypical case, a solution of the compound of formula (XXXXIX) wherein P¹and P² taken together are dimethylmethylene in a suitable solvent suchas methanol may treated with an acid such as pyridiniumpara-toluenesulphonate to give a compound of formula (XXXXIX) wherein P¹and P² are both replaced by H which may be subsequently reprotected withother functionality. For instance, the compound of formula (XXXXIX)wherein P¹ and P² are both replaced by H may be dissolved in a suitablesolvent such as dichloromethane and the resulting solution may betreated with an acid acceptor, such as pyridine, and benzoyl chloride togive a compound of formula (XXXXIX) wherein P¹ and P² are each benzoyl.Compounds of the formula (XXXXX) are known in the art (see, for example,J. Am. Chem. Soc., 1958, 80, 5168).

[0180] Compounds of the formula (XXXXXI) are either commerciallyavailable or easily prepared by methods well known to the person skilledin the art.

[0181] Compounds of the formula (VI), as used in Schemes 1, 4 and 5, areeither commercially available or easily prepared by methods well knownto the person skilled in the art.

[0182] 3. Compounds of the formula (I) in which R⁴ is —(C₂-C₆alkylene)—NR¹¹R^(a), wherein R^(a) is —CONR⁹R⁹, —COOR¹⁰, —COR¹⁰, —SO₂R¹⁰or —SO₂NR⁹R⁹, may be prepared by the derivatisation of an amine of theformula

[0183] with a suitable acylating or sulphonylating agent. For example,compounds of the formula (I) in which R⁴ is —(C₂-C₆ alkylene)—NR¹¹COR¹⁰may be prepared by the reaction of a compound of the formula (XXXXXII)with an acid chloride of the formula

R¹⁰COCl  (XXXXXIII).

[0184] In a typical procedure, a solution of the compound of the formula(XXXXXII) in a suitable solvent, such as a mixture of ethyl acetate andN-methylpyrrolidinone, is treated with a suitable base, preferably atrialkylamine base such as triethylamine, and the compound of theformula (XXXXXIII). As a further example, compounds of the formula (I)in which R⁴ is —(C₂-C₆ alkylene)—NR¹¹SO₂R¹⁰ may be prepared by thereaction of a compound of the formula (XXXXXII) with a compound of theformula

R¹⁰SO₂Cl  (XXXXXIV).

[0185] In a typical procedure, a solution of the compound of the formula(XXXXXII) in a suitable solvent, such as a mixture of ethyl acetate andN-methylpyrrolidinone, is treated with a suitable base, preferably atrialkylamine base such as triethylamine, and the compound of theformula (XXXXXIV).

[0186] Compounds of the formula (XXXXXII) may be prepared by analogywith the methods presented above for the preparation of compounds of theformula (I). Compounds of the formula (XXXXXIII) or (XXXXXIV) are eithercommercially available or are easily prepared by methods well known tothe skilled man.

[0187] A pharmaceutically acceptable salt of a compound of the formula(I) may be readily prepared by mixing together solutions of a compoundof the formula (I) and the desired acid or base, as appropriate. Thesalt may precipitate from solution and be collected by filtration or maybe recovered by evaporation of the solvent.

[0188] The anti-inflammatory properties of the compounds of the formula(I) are demonstrated by their ability to inhibit neutrophil functionwhich indicates A2a receptor agonist activity. This was evaluated bydetermining the compound profile in an assay where superoxide productionwas measured from neutrophils activated by fMLP. Neutrophils wereisolated from human peripheral blood using dextran sedimentationfollowed by centrifugation through Ficoll-Hypaque solution. Anycontaminating erythrocytes in the granulocyte pellet were removed bylysis with ice-cold distilled water. Superoxide production from theneutrophils was induced by fMLP in the presence of a primingconcentration of cytochalasin B. Adenosine deaminase was included in theassay to remove any endogenously produced adenosine that might suppresssuperoxide production. The effect of the compound on the fMLP-inducedresponse was monitored colorometrically from the reduction of cytochromeC within the assay buffer. The potency of the compounds was assessed bythe concentration giving 50% inhibition (IC₅₀) compared to the controlresponse to fMLP.

[0189] The compounds of the formula (I) can be administered alone butwill generally be administered in admixture with a suitablepharmaceutical excipient, diluent or carrier selected with regard to theintended route of administration and standard pharmaceutical practice.

[0190] For example, the compounds of the formula (I) can be administeredorally, buccally or sublingually in the form of tablets, capsules,multi-particulates, gels, films, ovules, elixirs, solutions orsuspensions, which may contain flavouring or colouring agents, forimmediate-, delayed-, modified-, sustained-, pulsed- orcontrolled-release applications. The compounds of the formula (I) mayalso be administered as fast-dispersing or fast-dissolving dosage formsor in the form of a high energy dispersion or as coated particles.Suitable formulations of the compounds of the formula (I) may be incoated or uncoated form, as desired.

[0191] Such solid pharmaceutical compositions, for example, tablets, maycontain excipients such as microcrystalline cellulose, lactose, sodiumcitrate, calcium carbonate, dibasic calcium phosphate, glycine andstarch (preferably corn, potato or tapioca starch), disintegrants suchas sodium starch glycollate, croscarmellose sodium and certain complexsilicates, and granulation binders such as polyvinylpyrrolidone,hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC),sucrose, gelatin and acacia. Additionally, lubricating agents such asmagnesium stearate, stearic acid, glyceryl behenate and talc may beincluded.

GENERAL EXAMPLE

[0192] A formulation of the tablet could typically contain between about0.01 mg and 500 mg of active compound whilst tablet fill weights mayrange from 50 mg to 1000 mg. An example of a formulation for a 10 mgtablet is illustrated below: Ingredient % w/w Compound of the formula(I) or salt 10.000* Lactose 64.125 Starch 21.375 Croscarmellose sodium 3.000 Magnesium Stearate  1.500

[0193] The tablets are manufactured by a standard process, for example,direct compression or a wet or dry granulation process. The tablet coresmay be coated with appropriate overcoats.

[0194] Solid compositions of a similar type may also be employed asfillers in gelatin or HPMC capsules. Preferred excipients in this regardinclude lactose, starch, a cellulose, milk sugar or high molecularweight polyethylene glycols. For aqueous suspensions and/or elixirs, thecompounds of the formula (I) may be combined with various sweetening orflavouring agents, colouring matter or dyes, with emulsifying and/orsuspending agents and with diluents such as water, ethanol, propyleneglycol and glycerin, and combinations thereof.

[0195] The compounds of the formula (I) can also be administeredparenterally, for example, intravenously, intra-arterially,intraperitoneally, intrathecally, intraventricularly, intraurethrally,intrasternally, intracranially, intramuscularly or subcutaneously, orthey may be administered by infusion or needleless injection techniques.For such parenteral administration they are best used in the form of asterile aqueous solution which may contain other substances, forexample, a co-solvent and/or enough salts or glucose to make thesolution isotonic with blood. The aqueous solutions should be suitablybuffered (preferably to a pH of from 3 to 9), if necessary. Thepreparation of suitable parenteral formulations under sterile conditionsis readily accomplished by standard pharmaceutical techniques well-knownto those skilled in the art.

[0196] For oral and parenteral administration to human patients, thedaily dosage level of the compounds of the formula (I) will usually befrom 0.00001 to 100 mg/kg, preferably from 0.0001 to 100 mg/kg (insingle or divided doses).

[0197] Thus tablets or capsules of the compound of the formula (I) maycontain from 0.01 to 500 mg of active compound for administration singlyor two or more at a time, as appropriate. The physician in any eventwill determine the actual dosage which will be most suitable for anyindividual patient and it will vary with the age, weight and response ofthe particular patient. The above dosages are exemplary of the averagecase. There can, of course, be individual instances where higher orlower dosage ranges are merited and such are within the scope of thisinvention.

[0198] The compounds of formula (I) can also be administeredintranasally or by inhalation and are conveniently delivered in the formof a dry powder inhaler or an aerosol spray presentation from apressurised container, pump, spray, atomiser (preferably an atomiserusing electrohydrodynamics to produce a fine mist) or nebuliser, with orwithout the use of a suitable propellant, e.g. dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkanesuch as 1,1,1,2-tetrafluoroethane (HFA 134A [trade mark]) or1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA [trade mark]), carbondioxide, a further perfluorinated hydrocarbon such as Perflubron (trademark) or other suitable gas. In the case of a pressurised aerosol, thedosage unit may be determined by providing a valve to deliver a meteredamount. The pressurised container, pump, spray, atomiser or nebulisermay contain a solution or suspension of the active compound, e.g. usinga mixture of ethanol (optionally aqueous ethanol) or a suitable agentfor dispersing, solubilising or extending release and the propellant asthe solvent, which may additionally contain a lubricant, e.g. sorbitantrioleate. Capsules, blisters and cartridges (made, for example, fromgelatin or HPMC) for use in an inhaler or insufflator may be formulatedto contain a powder mix of a compound of the formula (I) and a suitablepowder base such as lactose or starch and a performance modifier such asL-leucine, manitol or magnesium stearate.

[0199] A suitable solution formulation for use in an atomiser usingelectrohydrodynamics to produce a fine mist may contain from 1 gg to 10mg of a compound of the formula (I), or a salt thereof, and theactuation volume may vary from 1 to 100 μl. A typical formulation maycomprise a compound of the formula (I) or salt thereof, propyleneglycol, sterile water, ethanol and sodium chloride.

[0200] Aerosol or dry powder formulations are preferably arranged sothat each metered dose or “puff” contains from 1 to 4000 μg of acompound of the formula (I) for delivery to the patient. The overalldaily dose with an aerosol will be in the range of from 1 μg to 20 mgwhich may be administered in a single dose or, more usually, in divideddoses throughout the day.

[0201] Alternatively, the compounds of the formula (I) can beadministered in the form of a suppository or pessary, or they may beapplied topically in the form of a lotion, solution, cream, ointment ordusting powder. The compounds of the formula (I) may also be dermally ortransdermally administered, for example, by the use of a skin patch.They may also be administered by the pulmonary, vaginal or rectalroutes.

[0202] For application topically to the skin, the compounds of theformula (I) can be formulated as a suitable ointment containing theactive compound suspended or dissolved in, for example, a mixture withone or more of the following: mineral oil, liquid petrolatum, whitepetrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound,emulsifying wax and water. Alternatively, they can be formulated as asuitable lotion or cream, suspended or dissolved in, for example, amixture of one or more of the following: mineral oil, sorbitanmonostearate, a polyethylene glycol, liquid paraffin, polysorbate 60,cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol andwater.

[0203] The compounds of the formula (I) may also be used in combinationwith a cyclodextrin. Cyclodextrins are known to form inclusion andnon-inclusion complexes with drug molecules. Formation of adrug-cyclodextrin complex may modify the solubility, dissolution rate,bioavailability and/or stability property of a drug molecule.Drug-cyclodextrin complexes are generally useful for most dosage formsand administration routes. As an alternative to direct complexation withthe drug the cyclodextrin may be used as an auxiliary additive, e.g. asa carrier, diluent or solubiliser. Alpha-, beta- and gamma-cyclodextrinsare most commonly used and suitable examples are described inWO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.

[0204] It is to be appreciated that all references herein to treatmentinclude curative, palliative and prophylactic treatment.

[0205] Thus the invention provides:

[0206] (i) a compound of the formula (I) or a pharmaceuticallyacceptable salt or solvate thereof;

[0207] (ii) a process for the preparation of a compound of the formula(I) or a pharmaceutically acceptable salt or solvate thereof;

[0208] (iii) a pharmaceutical composition including a compound of theformula (I) or a pharmaceutically acceptable salt or solvate thereof,together with a pharmaceutically acceptable excipient, diluent orcarrier;

[0209] (iv) a compound of the formula (I) or a pharmaceuticallyacceptable salt, solvate or composition thereof, for use as amedicament;

[0210] (v) the use of a compound of the formula (I) or of apharmaceutically acceptable salt, solvate or composition thereof, forthe manufacture of a medicament having A2a receptor agonist activity;

[0211] (vi) the use of a compound of the formula (I) or of apharmaceutically acceptable salt, solvate or composition thereof, forthe manufacture of an anti-inflammatory agent;

[0212] (vii) the use of a compound of the formula (I) or of apharmaceutically acceptable salt, solvate or composition thereof, forthe manufacture of a medicament for the treatment of a respiratorydisease;

[0213] (viii) use as in (vii) where the disease is selected from thegroup consisting of adult respiratory distress syndrome (ARDS),bronchitis, chronic bronchitis, chronic obstructive pulmonary disease,cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitisand rhinitis;

[0214] (ix) the use of a compound of the formula (I) or of apharmaceutically acceptable salt, solvate or composition thereof, forthe manufacture of a medicament for the treatment of septic shock, maleerectile dysfunction, hypertension, stroke, epilepsy, cerebralischaemia, peripheral vascular disease, post-ischaemic reperfusioninjury, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis,dermatitis, allergic dermatitis, eczema, ulcerative colitis, Crohnsdisease, inflammatory bowel disease, Heliobacter pylori gastritis,non-Heliobacter pylor gastritis, non-steroidal anti-inflammatorydrug-induced damage to the gastro-intestinal tract or a psychoticdisorder, or for wound healing;

[0215] (x) a method of treatment of a mammal, including a human being,with a A2a receptor agonist including treating said mammal with aneffective amount of a compound of the formula (I) or with apharmaceutically acceptable salt, solvate or composition thereof;

[0216] (xi) a method of treatment of a mammal, including a human being,to treat an inflammatory disease including treating said mammal with aneffective amount of a compound of the formula (I) or with apharmaceutically acceptable salt, solvate or composition thereof;

[0217] (xii) a method of treatment of a mammal, including a human being,to treat a respiratory disease including treating said mammal with aneffective amount of a compound of the formula (I) or with apharmaceutically acceptable salt, solvate or composition thereof;

[0218] (xiii) a method as in (xii) where the disease is selected fromthe group consisting of adult respiratory distress syndrome (ARDS),bronchitis, chronic bronchitis, chronic obstructive pulmonary disease,cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitisand rhinitis;

[0219] (xiv) a method of treatment of a mammal, including a human being,to treat septic shock, male erectile dysfunction, hypertension, stroke,epilepsy, cerebral ischaemia, peripheral vascular disease,post-ischaemic reperfusion injury, diabetes, rheumatoid arthritis,multiple sclerosis, psoriasis, dermatitis, allergic dermatitis, eczema,ulcerative colitis, Crohns disease, inflammatory bowel disease,Heliobacter pylori gastritis, non-Heliobacter pylori gastritis,non-steroidal anti-inflammatory drug-induced damage to thegastrointestinal tract or a psychotic disorder, or for wound healing,including treating said mammal with an effective amount of a compound ofthe formula (I) or with a pharmaceutically acceptable salt, solvate orcomposition thereof; and

[0220] (xv) certain novel intermediates disclosed herein.

[0221] The following Examples illustrate the preparation of thecompounds of the formula (I).

[0222]¹H Nuclear magnetic resonance (NMR) spectra were in all casesconsistent with the proposed structures. Characteristic chemical shifts(δ) are given in parts-per-million downfield from tetramethylsilaneusing conventional abbreviations for designation of major peaks: e.g. s,singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad.The mass spectra (m/z) were recorded in either thermospray orelectrospray ionisation mode. The following abbreviations have been usedfor common solvents: CDCl₃, deuterochloroform; D₆DMSO,deuterodimethylsulphoxide; CD₃OD, deuteromethanol; THF, tetrahydrofuran.The reagent ‘0.88 concentrated aqueous ammonia’ is a concentratedsolution of ammonia in water possessing a specific gravity of 0.88.Where thin layer chromatography (TLC) has been used it refers to silicagel TLC using silica gel 60 F₂₅₄ plates, R_(f) is the distance travelledby a compound divided by the distance travelled by the solvent front ona TLC plate.

Example 1N-({9-[(2R,3R,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl)-N′-[2-(diisopropylamino)ethyl]urea

[0223]

[0224] N-[2-(Diisopropylamino)ethyl]-1H-imidazole-1-carboxamide (84 mg,0.35mmol) (Preparation 27) was added to a stirred solution of(2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(hydroxymethyl)tetrahydro-3,4-furandiol(150 mg, 0.35mmol) (Preparation 2) in dichloromethane (5 ml) at roomtemperature. The reaction was heated under reflux for 1 hour and thentoluene (5 ml) and isopropanol (2 ml) were added. The dichloromethanewas boiled off and the reaction was then heated under reflux for 1 hour.The reaction mixture was allowed to cool to room temperature and thesolvent was removed under reduced pressure. The residue was purified bycolumn chromatography on silica gel eluting withdichloromethane:methanol:0.88 concentrated aqueous ammonia (95:5:0.5 byvolume increasing to 80:20:2 by volume). This gave the title compound asa foam (60 mg).

[0225] δ_(H) (400MHz; CD₃OD): 8.05 (1H, s), 7.35-7.20 (8H, m), 7.15-7.10(2H, m), 5.90-5.85 (1H, m), 4.75-4.70 (1H, m), 4.50-4.45 (1H, m),4.40-4.20 (5H, m), 4.15-4.10 (1H, m), 3.90-3.80 (1H, m), 3.70-3.65 (1H,m), 3.10-3.00 (2H, m), 3.00-2.90 (2H, m), 2.50-2.40 (2H, m), 1.00-0.90(12H, m).

Example 2N-({9-[(2R,3R,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl)-N′-[2-(1-piperidinyl)ethyl]urea

[0226]

[0227] A solution of(2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-[(2,2-diphenylethyl)amino]-2-{[({[2-(1-piperidinyl)ethyl]amino}carbonyl)amino]methyl}-9H-purin-9-yl)tetrahydro-3-furanylacetate (100 mg, 0.13mmol) (Preparation 6) in methanol (50 ml) wassaturated with ammonia gas and then left to stand for 3 hours. Thesolvent was removed under reduced pressure to give a residue that waspurified by elution through a plug of silica gel with dichloromethane:methanol:0.88 concentrated aqueous ammonia (90:10:1 by volume) to givethe title compound as a foam (45 mg).

[0228] m/z: MH⁺ 631.

[0229] δ_(H) 400 MHz; CD₃OD): 8.15 (1H, s), 7.40-7.15 (10H, m),6.00-5.90 (1H, m), 4.90-4.70 (signal obscured by HOD in CD₃OD),4.60-4.10 (7H, m), 3.90-3.80 (1H, m), 3.80-3.70 (1H, m), 3.30-3.20 (2H,m), 2.55-2.35 (6H, m), 1.65-1.40 (6H, m).

Example 3(2S,3S,4R,5R)-5-{2-{[({[2-(Diisopropylamino)ethyl]amino}carbonyl)amino]methyl}-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide

[0230]

[0231] N-[2-(Diisopropylamino)ethyl]-1H-imidazole-1-carboxamide (84 mg,0.35mmol) (Preparation 27) was added to a stirred suspension of(2S,3S,4R,5R)-5-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide(100 mg, 0.23mmol) (Preparation 11) in dichloromethane (5 ml) at roomtemperature. The reaction was then heated to reflux and a drop ofisopropanol was added to help dissolve the reagents. The reactionmixture was heated under reflux for 20 minutes and then toluene (5 ml)was added. The dichloromethane was boiled off and the reaction was thenheated under reflux for 30 minutes. The reaction mixture was allowed tocool to room temperature and the solvent was removed under reducedpressure. The residue was purified by column chromatography on silicagel eluting with dichloromethane: methanol:0.88 concentrated aqueousammonia (95:5:0.5 by volume increasing to 80:20:2 by volume). Thesolvent was removed under reduced pressure to give a yellow oil. The oilwas dissolved in dichloromethane (2 ml) and diethylether was added toinduce crystallisation. Filtration gave the title compound as a whitesolid (70 mg).

[0232] δ_(H)(400 MHz; CD₃OD): 8.20 (1H, s), 7.40-7.10 (10H, m),6.10-6.00 (1H, m), 4.90-4.80 (1H obscured by HOD in MeOH), 4.55-4.20(7H, m), 3.40-3.10 (6H, m), 2.75-2.60 (2H, m), 1.20-1.00 (15H, m).

Example 4(2S,3S,4R,5R)-5-(6-[(2,2-Diphenylethyl)amino]-2-{[({[2-(1-Piperidinyl)ethyl]amino}carbonyl)amino]methyl}-9H-purin-9-yl)-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide

[0233]

[0234] Potassium carbonate (20 mg, 0.14 mmol) was added to a solution of(2S,3S,4R,5R)-4-(benzoyloxy)-5-(6-[(2,2-diphenylethyl)amino]-2-{[({[2-(1-piperidinyl)ethyl]amino}carbonyl)amino]methyl}-9H-purin-9-yl)-2-[(ethylamino)carbonyl]tetrahydro-3-furanylbenzoate (100 mg, 0.13 mmol) (Preparation 14) in methanol (10 ml). Thereaction mixture was stirred at room temperature for 2 hours. Morepotassium carbonate (20 mg, 0.14 mmol) was then added and the reactionmixture was heated to 60° C. for 2 hours. The solvent was removed underreduced pressure to give a residue that was slurried with acetone andfiltered. The filtrate was evaporated under reduced pressure and theresidue was partially purified by column chromatography on silica geleluting with dichloromethane:methanol:0.88 concentrated aqueous ammonia(90:10:1 by volume). The residue after solvent evaporation under reducedpressure was repurified by more column chromatography on silica geleluting with dichloromethane:methanol:0.88 concentrated aqueous ammonia(90:10:1 by volume). The solvent was removed by evaporation underreduced pressure to give the title compound as a foam (17 mg).

[0235] m/z: MH⁺ 673.

[0236] δ_(H) 400 MHz; CD₃OD): 8.20 (1H, s), 7.40-7.15 (10H, m),6.05-6.00 (1H, m), 4.90-4.80 (1H obscured by HOD in MeOH), 4.55-4.20(7H, m), 3.40-3.20 (4H, m), 2.55-2.40 (6H, m), 1.70-1.50 (4H, m),1.50-1.40 (2H, m), 1.15-1.05 (3H, m).

Example 5(2S,3S,4R,5R)-5-{2-{[((E)-(Cyanoimino){[2-(1-piperidinyl)ethyl]amino}methyl)amino]methyl}-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide

[0237]

[0238] Dimethyl cyanodithioimidocarbonate (77 mg, 0.48 mmol) was addedto a solution of(2S,3S,4R,5R)-5-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide(250 mg, 0.48 mmol) (Preparation 11) in ethanol (10 ml). The reactionmixture was stirred for 3 hours at room temperature and then2-aminoethylpiperidine (88μl, 0.68 mmol) was added. The reaction mixturewas heated under reflux for 2 hours, more 2-aminoethylpiperidine (0.17ml, 1.2 mmol) was added and then the reaction mixture was heated underreflux for a further 4 hours. The reaction was cooled and evaporated todryness and the residue was purified by flash chromatography on silicagel eluting with dichloromethane:methanol (98:2 by volume) increasing inpolarity to dichloromethane methanol:0.88 concentrated aqueous ammonia(90:10:1 by volume) to give the title compound (64 mg) a foam.

[0239] m/z MH⁺ 696.

[0240] δ_(H)(400 MHz; CDCl₃): 8.30 (1H, s), 8.20 (1H, s), 7.85 (1H, s),7.35-7.05 (10H, m), 6.95 (1H, bs), 5.95-5.85 (1H, m), 5.60-5.55 (1H, m),5.45-5.40 (1H, m), 4.60-4.45 (2H, m), 4.40-4.35 (1H, m), 4.25-4.20 (1H,m), 4.15-4.00 (3H, m), 3.35-3.05 (4H, m signal partially obscured by HODin DMSO), 2.40-2.15 (6H, m), 1.40-1.20 (6H, m).

Example 6(2S,3S,4R,5R)-5-{2-({[(Benzylamino)carbonyl]amino}methyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide

[0241]

[0242] Benzylisocyanate (26 mg, 0.30 mmol) was added to a solution of(2S,3S,4R,5R)-5-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide(Preparation 11) in dichloromethane (2 ml). The reaction mixture wasstirred for 16 hours at room temperature and allowed to evaporate.Ethanol (2 ml) was added and then aqueous hydrochloric acid (1M, 1 ml)was added. The reaction mixture was stirred at 60° C. for 6 hours, thenallowed to cool to room temperature and left for a further 16 h. Moreaqueous hydrochloric acid (1 M, 0.5 ml) was added and the reactionmixture was stirred at room temperature for a further 4 h. The solventwas removed under reduced pressure and the residue was purified bycolumn chromatography on silica gel eluting with dichloromethane:methanol (95:5 by volume) increasing in polarity todichloromethane:methanol (90:10 by volume). The material obtained wasimpure and hence was repurified by column chromatography on silica geleluting with dichloromethane:methanol (95:5 by volume) increasing inpolarity to dichloromethane:methanol (90:10 by volume) to give the titlecompound as a solid (85 mg).

[0243] δ_(H) (300 MHz; D₆DMSO): 8.35-8.25 (2H, m), 7.80-7.75 (1H, m),7.40-7.10 (15H, m), 6.80-6.70 (1H, m), 6.40-6.30 (1H, m), 6.00-5.90 (1H,m), 5.65-5.60 (1H, m), 5.50-5.40 (1H, m), 4.65-4.55 (2H, m), 4.35-4.05(8H, m), 3.25-3.05 (2H, m), 1.05-0.95 (3H, m).

Example 7(2S,3S,4R,5R)-5-{2-({[(Cyclohexylamino)carbonyl]amino}methyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide

[0244]

[0245] The compound was prepared from cyclohexylisocyanate and(2S,3S,4R,5R)-5-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide(Preparation 11) according to the procedure used in Example 6.

[0246] m/z MH⁺ 644.

[0247] δ_(H) (300 MHz; d₆DMSO): 8.40-8.20 (2H, m), 7.80-7.70 (1H, m),7.40-7.05 (10H, m), 6.25-5.85 (3H, m), 5.65-5.55 (1H, m), 5.55-5.40 (1H,m), 4.70-4.45 (2H, m), 4.35-4.00 (5H, m), 3.50-3.00 (3H, m), 1.85-1.40(5H, m), 1.30-1.00 (8H, m).

Example 8(2S,3S,4R,5R)-5-{2-({[({2-[Benzoyl(isopropyl)amino]ethyl}amino)carbonyl]amino}methyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide

[0248]

[0249] Benzoyl chloride (19 mg, 0.14 mmol) was added to a stirredsolution of(2S,3S,4R,5R)-5-(6-[(2,2-diphenylethyl)amino]-2-{[({[2-(isopropylamino)ethyl]amino}carbonyl)amino]methyl}-9H-purin-9-yl)-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide(80 mg, 0.12 mmol) (Preparation 12) and triethylamine (0.034 ml, 0.25mmol) in ethyl acetate (5 ml) and N′-methylpyrrolidinone (0.2 ml) atroom temperature. The reaction mixture was stirred for 96 hours, washedwith water (2 ml) and evaporated under reduced pressure. The residue waspurified by column chromatography on silica gel eluting withdichloromethane:methanol:0.88 concentrated aqueous ammonia (90:10:1 byvolume) increasing in polarity to dichloromethane:methanol:0.88concentrated aqueous ammonia (80:20:3 by volume) to give the titlecompound as a foam (35 mg).

[0250] m/z MH⁺ 787.

[0251] δ_(H) (400 MHz; CD₃OD): 8.20 (1H, s), 7.50-7.15 (15H, m),6.05-6.00 (1H, m), 4.90-4.80 (1H, m), 4.55-4.20 (7H, m), 3.95-3.85 (1H,m), 3.50-3.20 (6H, m), 1.20-1.00 (9H, m).

Example 9(2S,3S,4R,5R)-5-[6-[(2,2-Diphenylethyl)amino]-2-({[({2-[isopropyl(phenylsulfonyl)amino]ethyl}amino)carbonyl]amino}methyl)-9H-purin-9-yl]-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide

[0252]

[0253] The title compound was prepared from(2S,3S,4R,5R)-5-(6-[(2,2-diphenylethyl)amino]-2-{[({[2-(isopropylamino)ethyl]amino}carbonyl)amino]methyl}-9H-purin-9-yl)-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide(80 mg, 0.12 mmol) (Preparation 12) and benzenesulphonyl chloride(0.0017 ml, 0.14 mmol) by a similar method to that of Example 8.

[0254] m/z MH⁺ 787.

[0255] δ_(H) (400 MHz; CD₃OD): 8.15 (1H, s), 7.80-7.75 (2H, m),7.60-7.50 (1H, m), 7.50-7.40 (2H, m), 7.30-7.15 (8H, m), 7.15-7.05 (2H,m), 6.05-5.95 (1H, m), 4.50-4.30 (5H, m), 4.30-4.20 (2H, m), 4.05-3.95(1H, m), 3.40-3.20 (4H, m), 3.0-3.10 (2H, m), 1.10-1.00 (3H, m),1.00-0.90 (6H, m).

Example 10NA-({9-[(2R,3R,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl)-N-methyl-N-[2-(2-pyridinyl)ethyl]urea

[0256]

[0257] N,O-Bistrimethylsilylacetamide (0.5 ml, 2.02 mmol) was added to asuspension ofN′-({6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl)-N-methyl-N-[2-(2-pyridinyl)ethyl]urea(0.16 g, 0.31mol) (Preparation 26) in 1,1,1-trichloroethane (15 ml). Thesuspension was heated to reflux. When all suspended solid had dissolvedthe reaction mixture was allowed to cool to room temperature and thesolvent was removed under reduced pressure. The residue was twicedissolved in toluene (50 ml) and the solvent was removed under reducedpressure. The residue was then dissolved in toluene (15 ml) and(2R,3R,4R,5S)-4,5-bis(acetyloxy)-2-[(acetyloxy)methyl]tetrahydro-3-furanylacetate (0.112 g, 0.36mol) was added. The solution was stirred at roomtemperature and trimethylsilyltrifluoromethanesulphonate (0.17 ml, 0.94mmol) was added. The resulting solution was heated under reflux for 2hours and then allowed to cool to room temperature. The reaction mixturewas diluted by the addition of ethyl acetate (75 ml) and then washedwith saturated aqueous sodium hydrogen carbonate solution (two portionsof 30 ml) and saturated aqueous sodium chloride solution (30 ml). Theorganic layer was dried over anhydrous magnesium sulphate. The solventwas removed under reduced pressure to give a solid that was purified bycolumn chromatography on silica gel eluting withdichloromethane:methanol:0.88 concentrated aqueous ammonia (97:3:0.5 byvolume). This material was dissolved in methanol (50 ml) and a stream ofammonia gas was passed through the solution until it was saturated. Thesolution was allowed to stand at room temperature for 4 hours. Thesolvent was removed under reduced pressure to give a residue that waspurified by flash chromatography on silica gel eluting withdichloromethane:methanol:0.88 concentrated aqueous ammonia (90:10:1 byvolume) to give the title compound (0.05 g) as a white solid.

[0258] m/z MH⁺ 639.

[0259] δ_(H) (300 MHz; CD₃OD): 8.45-8.40 (1H, m), 8.10 (1H, s),7.75-7.65 (1H, m), 7.35-7.10 (11H, m), 5.95-5.90 (1H, m), 4.80-4.75 (1H,m), 4.50-4.40 (3H, m), 4.40-4.20 (3H, m), 4.20-4.15 (1H, m), 3.90-3.85(1H, m), 3.75-3.70 (1H, m), 3.60-3.45 (2H, m), 3.00-2.90 (2H, m), 2.80(3H, s).

Examples 11-28

[0260] The following Examples were prepared by a similar method to thatof Example 3 using the stated starting materials. Exam- LRMS pleStructure (electro- Number (starting materials) ¹H-NMR (400 MHz) spray):m/z 11

δ_(H) (300MHz; CD₃OD): 8.20 (1H, s), 7.40-7.20 (15H, m), 7.20-7.10 (2H,m), 6.10-6.00 (1H, m), 4.55-4.20 (7H, m), 3.60-3.05 (3H, m), 2.90-2.80(2H, m), 2.20-2.10 (2H, m), 1.90-1.80 (2H, m), 1.55-1.40 (2H, m),1.15-1.05 (3H, m). 12

δ_(H) (300MHz; CD₃OD): 8.20 (1H, s), 7.40-7.25 (8H, m), 7.25-7.15 (2H,m), 6.05-6.00 (1H, m), 4.60-4.25 (7H, m), 3.40-3.20 (2H, m), 3.20-3.05(2H, m), 2.65-2.40 (4H, m), 2.40-2.20 (1H, m), 1.70-1.55 (1H, m),1.55-1.25 (6H, m), 1.15-1.05 (3H, m), 1.00-0.80 (12H, m). 13

δ_(H) (400MHz; CD₃OD): 8.05 (1H, s), 7.35-7.20 (8H, m), 7.20-7.10 (2H,m), 5.90-5.85 (1H, m), 4,75-4.70 (1H, m), 4.50-4.45 (1H, m), 4.40-4.20(5H, m), 4.10 (1H, s), 3.90-3.80 (1H, # m), 3.70-3.65 (1H, m), 3.10-3.00(2H, m), 2.50-2.35 (4H, m), 2.25-2.20 (1H, m), 1.60-1.50 (1H, m),1.50-1.30 (2H, m), 1.30-1.20 (4H, m), 0.90-0.80 (12H, m). [MH⁺] 703 14

δ_(H) (400MHz; CD₃OD): 8.10 (1H, s), 7.40-6.90 (14H, m), 5.95-5.85 (1H,m), 4.80-4.70 (1H, m), 4.50-4.10 (7H, m), 3.90-3.80 (1H, m), # 3.75-3.70(1H, m), 3.70-3.60 (2H, m), 3.40-3.25 (2H, m), 2.90-2.80 (2H, m),2.90-2.65 (2H, m), 2.65-2.55 (2H, m). [MH⁺] 679 15

δ_(H) (400MHz; CD₃OD): 8.10 (1H, s), 7.40-6.90 (14H, m), 5.95-5.85 #(1H, m), 4.80-4.70 (1H, m), 4.50-4.10 (7H, m), 3.90-3.80 (1H, m),3.75-3.70 (1H, m), 3.70-3.60 (2H, m), 3.40-3.25 (2H, m), 2.90-2.80 (2H,m), 2.80-2.65 (2H, m), 2.65-2.55 (2H, m). [MH⁺] 720 16

δ_(H) (400MHz; CD₃OD): 8.20 (1H, s), 7.35-7.25 (8H, m), 7.20-7.10 (2H,m), # 6.05-6.00 (1H, m), 4.55-4.30 (5H, m), 4.30-4.20 (2H, m), 3.40-3.20(4H, m), 2.70-2.60 (2H, m), 2.60-2.50 (4H, m), 1.50-1.40 (4H, m),1.40-1.25 (4H, m), 1.10-1.05 (3H, m), 0.95-0.85 (6H, m). [MH⁺] 716 17

δ_(H) (300MHz; CD₃OD): 8.20 (1H, s), 7.40-7.25 (8H, m), 7.20-7.15 (2H,m), # 6.05-6.00 (1H, m), 4.55-4.35 (7H, m), 4.35-4.20 (2H, m), 3.45-3.25(2H, m), 3.25-3.00 (4H, m), 2.60-2.50 (2H, m), 1.85-1.75 (2H, m),1.70-1.30 (6H, m), 1.20-1.10 (3H, m), 1.05-1.00 (6H, m). [MH⁺] 714 18

δ_(H) (400MHz; CDCl₃): D₂O exchange. 7.60 (1H, s), 7.35-7.15 (10H, m),5.70-5.65 (1H, m), 4.90-4.80 (1H, m), 4.50-4.10 (6H, m), 3.90-3.85 (1H,m), 3.75-3.65 (1H, m), 3.10-3.05 (2H, m), 3.05-2.95 (2H, m), 2.55-2.45(2H, m), # 1.80-1.65 (2H, m), 1.65-1.50 (2H, m), 1.50-1.40 (2H, m),1.40-1.25 (2H, m), 1.00-0.90 (6H, m). [MH⁺] 673 19

δ_(H) (400MHz; CD₃OD): 8.15-8.10 (1H, m), 8.05-8.00 (1H, m), 7.50-7.40(1H, m), 7.30-7.15 (8H, m), 7.15-7.05 (2H, m), 6.75-6.70 (1H, m),6.60-6.50 (1H, m), # 6.00-5.95 (1H, m), 4.45-3.95 (8H, m), 3.75-3.65(1H, m), 3.35-3.20 (2H, m), 2.95-2.85 (2H, m), 1.90-1.80 (2H, m),1.40-1.30 (2H, m), 1.10-1.00 (3H, m). [MH⁺] 721 20

δ_(H) (400MHz; CD₃OD): 8.20-810 (1H, m), 7.35-7.20 (8H, m), 7.20-7.10(2H, m), 6.05-5.95 (1H, m), 4.80-4.70 (1H, m), 4.60-4.40 (3H, # m),4.40-4.30 (2H, m), 4.30-4.15 (2H, m), 3.40-3.20 (5H, m), 3.10-3.00 (2H,m), 2.40-2.25 (6H, m), 1.60-1.45 (4H, m), 1,45-1.35 (2H, m), 1.15-1.00(3H, m). [MH⁺] 686 21

δ_(H) (400MHz; CD₃OD): 8.20-8.15 (1H, m), 7.35-7.20 (8H, m), 7.20-7.10(2H, m), 6.05-6.00 (1H, m), 4.55-4.30 (5H, m), 4.30-4.20 (2H, m),3.40-3.20 (2H, m), 3.10-3.05 (2H, m), 2.90-2.80 (1H, m), 2.70-2.65 (2H,m), 1.75-1.60 (4H, m), 1.60-1.50 (1H, m), 1.40-1.20 (4H, # m), 1.20-1.00(13H, m). [MH⁺] 742 22

δ_(H) (400MHz; CD₃OD): 8.10-8.05 (1H, m), 7.35-7.20 (8H, m), 7.20-7.10(2H, m), 5.95-5.90 (1H, m), 4.80-4.70 (1H, m), 4.55-4.10 (7H, m),3.90-3.80 (1H, m), # 3.75-3.70 (1H, m), 3.10-3.05 (2H, m), 2.90-2.80(1H, m), 2.70-2.65 (1H, m), 1.75-1.60 (4H, m), 1.60-1.50 (1H, m),1.40-1.20 (4H, m), 1.10 (9H, s), 1.10-0.95 (1H, m). 23

δ_(H) (400MHz; CD₃OD): 8.05-8.00 (2H, m), 7.50-7.40 (1H, m), 7.30-7.25(4H, m), 7.25-7.15 (4H, m), 7.10-7.05 (2H, m), 6.75-6.70 (1H, m),6.60-6.55 (1H, m), 5.90-5.85 (1H, m), 4.75-4.70 (1H, m), 4.50-4.40 (1H,m), # 4.40-4.35 (1H, m), 4.30-4.25 (1H, m), 4.25-4.20 (1H, m), 4.10 (1H,5), 4.05-4.00 (2H, m), 3.85-3.80 (1H, m), 3.70-3.65 (2H, m), 2.90-2.85(2H, m), 1.90-1.80 (2H, m), 1.40-1.25 (2H, m). [MH⁺] 680 24

δ_(H) (400MHz; CD₃OD): 8.10 (1H, s), 7.30-7.20 (13H, m), 7.20-7.10 (2H,m), 5.95-5.90 (1H, m), 4.75-4.70 (1H, m), 4.50-4.45 (1H, m), # 4.40-4.20(6H, m), 4.10 (1H, s), 3.90-3.80 (1H, m), 3.75-3.70 (1H, m), 3.45 (2H,m), 3.00-2.95 (2H, m), 2.85-2.80 (2H, m), 1.95-1.90 (2H, m), 1.65-1.60(2H, m), 1.45-1.35 (1H, m), 1.25-1.10 (2H, m). [MH⁺] 707 25

δ_(H) (400MHz; CDCl₃): D₂O exchanged 7.80 (1H, s), 7.20-7.05 (13H, m),7.05-7.00 (2H, m), 5.80-5.75 (1H, m), 4.70-4.65 (1H, m), 4.50-4.45 #(1H, m), 4.35-4.20 (4H, m), 4.20-4.05 (2H, m), 3.40-3.45 (2H, m),3.25-3.15 (1H, m), 3.10-3.00 (1H, m), 2.95-2.80 (2H, m), 2.80-2.70 (2H,m), 1.90-1.80 (2H, m), 1.55-1.45 (2H, m), 1.35-1.25 (1H, m), 1.20-1.05(2H, m), 0.95-0.90 (3H, m). [MH⁺] 748 26

δ_(H) (400MHz; CD₃OD): 8.10-8.05 (1H, m), 7.50-7.40 (2H, m), 7.30-7.15(7H, m), 7.15-7.05 (3H, m), 6.05-5.95 (1H, m), 4.85-4.80 (1H, m),4.50-4.30 (5H, m), 4.30-4.20 (2H, m), 3.35-3.20 (2H, # m), 3.20-3.10(2H, m), 2.80-2.60 (3H, m), 1.35-1.30 (6H, m), 1.10-1.00 (3H, m),0.90-0.80 (6H, m). [MH⁺] 765 27

δ_(H) (400MHz; CD₃OD): 8.05 (1H, s), 7.35-7.20 (12H, m), 7.20-7.10 (3H,m), 6.10-6.05 (1H, m), 4.75-4.70 # (1H, m), 4.50-4.40 (1H, m), 4.35-4.20(5H, m), 4.10-4.05 (1H, m), 3.90-3.75 (2H, m), 3.70-3.60 (3H, m),0.95-0.90 (3H, m), 0.85-0.80 (3H, m). 28

δ_(H) (400MHz; CDCl₃): 7.50 (1H, s), 7.30-7.10 (10H, m), 5.70-5.60 (1H,m), 4.45-4.35 (1H, m), 4.35-4.20 (3H, m), 4.20-4.15 (1H, m), 4.15-4.00(1H, m), 3.90-3.80 (1H, m), # 3.70-3.60 (1H, m), 3.15-2.95 (3H, m),2.50-2.40 (2H, m), 1.70-1.60 (4H, m), 1.60-1.45 (4H, m), 1.45-1.35 (4H,m), 1.35-1.20 (4H, m). [MH⁺] 699

Example 29N-({9-[(2R,3R,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-6-[(9H-fluoren-9-ylmethyl)amino]-9H-purin-2-yl}methyl)-Ar-[2-(diisopropylamino)ethyl]urea

[0261]

[0262] The title compound was prepared from(2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(9H-fluoren-9-ylmethyl)amino]-9H-purin-9-yl}-5-(hydroxymethyl)tetrahydro-3,4-furandiol(Preparation 13) andN-[2-(diisopropylamino)ethyl]-1H-imidazole-1-carboxamide (Preparation27) in a similar procedure to Example 3.

[0263] m/z MH⁺ 645.

[0264] δ_(H) (400 MHz; CD₃OD): 8.20 (1H, m), 7.85-7.75 (2H, m),7.70-7.60 (2H, m), 7.40-7.20 (4H, m), 6.00-5.90 (1H, m), 4.40-4.35 (1H,m), 4.35-4.30 (1H, m), 4.20-4.00 (3H, m), 3.90-3.70 (4H, m).

Example 30N-({(9-[(2R,3R,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl)-N′-[2-(2,2,6,6-tetramethyl-1-piperidinyl)ethyl]urea

[0265]

[0266] 2-(2,2,6,6-Tetramethyl-1-piperidinyl)ethanamine (0.11 g, 0.6mmol) (Preparation 43) was added to a stirred solution ofN′N′-carbonyldiimidazole in tetrahydrofuran (5 ml) at room temperature.The reaction mixture was stirred for 16 hours at room temperature. Thesolvent was evaporated and the residue was dissolved in ethyl acetate(30 ml). The resulting solution was washed with water (20 ml) and driedover anhydrous sodium sulphate. The solvent was evaporated to giveimpureN-[2-(2,2,6,6-tetramethyl-1-piperidinyl)ethyl]-1H-imidazole-1-carboxamideas a gum. This crude material (83 mg, 0.3 mmol) was added to a stirredsolution of(2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(hydroxymethyl)tetrahydro-3,4-furandiol(100 mg, 0.21 mmol) (Preparation 2) in toluene (5 ml) and isopropanol (1ml) at room temperature. The reaction mixture was heated under refluxfor 3 hours and then allowed to cool to room temperature. The solventwas evaporated under reduced pressure to give a residue that waspurified by column chromatography on silica gel eluting withdichloromethane:methanol 0.88 concentrated aqueous ammonia (95:5:0.5 byvolume) increasing in polarity to dichloromethane:methanol:0.88concentrated aqueous ammonia (90:10:1 by volume). The solvent wasevaporated under reduced pressure to give a residue that was found tostill be impure. The residue was repurified by column chromatography onsilica gel eluting with dichloromethane:methanol:0.88 concentratedaqueous ammonia (95:5:0.5 by volume) increasing in polarity todichloromethane:methanol:0.88 concentrated aqueous ammonia (90:10:1 byvolume). The solvent was removed under reduced pressure to give thetitle compound (22 mg) as a gum.

[0267] m/z MH⁺ 686.

[0268] δ_(H) (400 MHz; CD₃OD): 8.10 (1H, s), 7.35-7.20 (8H, m),7.20-7.10 (2H, m), 5 5.95-5.90 (1H, m), 4.75-4.70 (1H, m), 4.55-4.45(1H, m), 4.45-4.20 (5H, m), 4.20-4.10 (1H, m), 3.90-3.85 (1H, m),3.75-3.70 (1H, m), 3.15-3.05 (2H, m), 2.60-2.55 (2H, m), 1.60-1.50 (2H,m), 1.45-1.40 (4H, m), 1.05 (12H, s).

Example 31(2S,3S,4R,5R)-5-(6-[(2,2-Diphenylethyl)amino]-2-{[({[2-(4-isopropyl-1-piperidinyl)ethyl]amino}carbonyl)amino]methyl}-9H-purin-9-yl)-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide

[0269]

[0270] 2-(4-Isopropyl-1-piperidinyl)ethylamine (0.3 g, 1.76 mmol)(Preparation 57) was added to a stirred solution ofN′N′-carbonyldiimidazole (0.295 g, 1.82 mmol) in tetrahydrofuran (15ml). The reaction mixture was stirred for two hours. The solvent wasremoved under reduced pressure and the residue was partitioned betweenethyl acetate (40 ml) and water (20 ml). The organic layer was driedover anhydrous sodium sulphate and the solvent was removed to giveimpure N-[2-(4-isopropyl-1-piperidinyl)ethyl]-1H-imidazole-1-carboxamide(Preparation 28). This crude material was added to a solution of(2S,3S,4R,5R)-5-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide(130 mg, 0.25 mmol) (Preparation 11) in toluene (3 ml) and isopropylalcohol (1 ml) at room temperature. The reaction mixture was heatedunder reflux for 3 hours. The solvent was removed under reduced pressureand the residue was purified by column chromatography eluting withdichloromethane:methanol:0.88 concentrated aqueous ammonia (95:5:0.5 byvolume) increasing in polarity to dichloromethane:methanol:0.88concentrated aqueous ammonia (80:20:3 by volume). The solvent wasremoved under reduced pressure to give a residue that was impure. Thematerial was triturated with diethylether (5 ml) three times. Theinsoluble solid was repurified by column chromatography eluting withdichloromethane:methanol:0.88 concentrated aqueous ammonia (95:5:0.5 byvolume) increasing in polarity to dichloromethane:methanol:0.88concentrated aqueous ammonia (90:10:1 by volume). The solvent wasremoved under reduced pressure to give the title compound (37 mg) as afoam.

[0271] m/z MH⁺ 714.

[0272] δ_(H) (400 MHz; CD₃OD): 8.20 (1H, s), 7.40-7.20 (8H, m),7.20-7.10 (2H, m), 6.05-6.00 (1H, m), 4.55-4.20 (7H, m), 3.40-3.20 (4H,m), 3.05-2.85 (2H, m), 2.50-2.35 (2H, m), 2.00-1.85 (2H, m), 1.70-1.60(2H, m), 1.45-1.20 (3H, m), 1.10-0.95 (4H, m), 0.95-0.80 (6H, m).

Example 32(2S,3S,4R,5R)-5-(6-[(2,2-Diphenylethyl)amino]-2-{[({[2-(2,2,6,6-tetramethyl-1-piperidinyl)ethyl]amino}carbonyl)amino]methyl}-9H-purin-9-yl)-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide

[0273]

[0274] The title compound was prepared by a similar procedure to thatused in Example 30 using(2S,3S,4R,5R)-5-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide(Preparation 11) and 2-(2,2,6,6-tetramethyl-1-piperidinyl)ethanamine(Preparation 43).

[0275] m/z MH⁺ 728.

[0276] δ_(H) (400 MHz; CD₃OD): 8.20 (1H, s), 7.15-7.10 (4H, m),7.10-7.05 (4H, m), 7.20-7.15 (2H, m), 6.05-6.00 (1H, m), 4.55-4.40 (5H,m), 4.35-4.20 (2H, m), 3.40-3.20 (2H, m), 3.15-3.05 (2H, m), 2.65-2.55(2H, m), 1.60-1.50 (2H, m), 1.45-1.40 (4H, m), 1.15-1.05 (3H, m),1.05-1.00 (12H, m).

Example 33N-[(3R)-1-Benzylpyrrolidinyl]-N′-({9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl)urea

[0277]

[0278] (3R)-1-Benzyl-3-pyrrolidinamine (0.64 ml, 3.4 mmol) was added toa stirred solution of N′N′-carbonyldiimidazole (0.6 g, 3.7 mmol) indichloromethane (150 ml) at room temperature. The reaction mixture wasstirred at room temperature for 1 hour. Dichloromethane (100 ml) wasadded and the solution then washed three times with water (50 ml). Theorganic phase was washed twice with saturated aqueous sodium chloridesolution and then dried over anhydrous magnesium sulphate. The solventwas removed under reduced pressure to giveN-[(3R)-1-benzylpyrrolidinyl]-1H-imidazole-1-carboxamide (1.23 g) as animpure oil. This material (115 mg, 0.43 mmol) was added to a stirredsolution of(2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(hydroxymethyl)tetrahydro-3,4-furandiol(Preparation 2) (100 mg, 0.21 mmol) in toluene (10 ml) and isopropanol(2.5 ml) at room temperature. The reaction mixture was heated underreflux for 40 minutes and then allowed to cool to room temperature. Thesolvent was removed under reduced pressure and the residue was purifiedby column chromatography eluting with dichloromethane:methanol:0.88concentrated aqueous ammonia (95:5:0.5 by volume) increasing in polarityto dichloromethane:methanol:0.88 concentrated aqueous ammonia (90:10:1by volume). The solvent was removed under reduced pressure to give thetitle compound (138 mg).

[0279] δ_(H) (400 MHz; CD₃OD): 8.10 (1H, s), 7.30-7.20 (13H, m),7.20-7.10 (2H, m), 5.90-5.85 (1H, m), 4.80-4.75 (1H, m), 4.50-4.45 (1H,m), 4.45-4.10 (7H, m), 3.90-3.85 (1H, m), 3.75-3.70 (1H, m), 3.60-3.50(2H, m), 2.75-2.65 (2H, m), 2.50-2.40 (2H, m), 2.20-2.10 (1H, m),1.60-1.50 (1H, m).

Example 34(2S,3S,4R,5R)-5-{2-{[({[(3R)-1-Benzylpyrrolidinyl]amino}carbonyl)amino]methyl}-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide

[0280]

[0281] The title compound was prepared by a similar method to that ofExample 33 using(2S,3S,4R,5R)-5-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl)-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide(Preparation 11) and (3R)-1-benzyl-3-pyrrolidinamine.

[0282] δ_(H) (400 MHz; CD₃OD): 8.15 (1H, s), 7.35-7.20 (13H, m),7.20-7.10 (2H, m), 6.05-6.00 (1H, m), 4.85-4.80 (1H, m), 4.55-4.10 (7H,m), 3.60-3.50 (2H, m), 3.40-3.20 (2H, m), 2.80-2.60 (2H, m), 2.50-2.35(2H, m), 2.20-2.10 (1H, m), 1.65-1.45 (1H, m), 1.15-1.00 (3H, m).

Example 35(2S,3S,4R,5R)-5-(6-{[2,2-Bis(4-chlorophenyl)ethyl]amino}-2-{[({[2-(diisopropylamino)ethyl]amino}carbonyl)amino]methyl}-9H-purin-9-yl)-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide

[0283]

[0284](2R,3R,4S,5S)-4-(Benzoyloxy)-2-(6-{[2,2-bis(4-chlorophenyl)ethyl]amino}-2-cyano-9H-purin-9-yl)-5-[(ethylamino)carbonyl]tetrahydro-3-furanylbenzoate (220 mg, 0.28 mmol) (Preparation 68) was added to a saturatedsolution of ammonia in ethanol (15 ml). 10% Palladium on carbon (40 mg)was added and the suspension was stirred under an atmosphere of hydrogengas (413.7 kPa, 60 psi) at room temperature for 16 hours. The reactiontemperature was then stirred at 60° C. under an atmosphere of hydrogengas (413.7 kPa, 60 psi) for a further 48 hours. The reaction mixture wasfiltered through Arbocel (Trade Mark) and the solvent was removed underreduced pressure. The crude residue was dissolved in toluene (8 ml) andisopropyl alcohol (2 ml) andN-[2-(diisopropylamino)ethyl]-1H-imidazole-1-carboxamide (50 mg, 0.21mmol) (Preparation 27) were added. The solution was heated under refluxfor 3 hours. The solvent was removed under reduced pressure and theresidue was purified by column chromatography on silica gel eluting withdichloromethane methanol:0.88 concentrated aqueous ammonia (90:10:2 byvolume). The solvent was removed under reduced pressure give a productthat was contaminated with imidazole. The product was dissolved indichloromethane (60 ml) and the resulting solution was washed threetimes with water (10 ml) and dried over anhydrous magnesium sulphate.The solvent was removed under reduced pressure to give the titlecompound (53 mg) as a foam.

[0285] m/z MH⁺ 756.

[0286] δ_(H) (400 MHz; CD₃OD): 8.20 (1H, s), 7.40-7.20 (8H, m),6.05-6.00 (1H, m), 4.55-4.20 (7H, m), 3.40-3.25 (2H, m), 3.20-3.05 (4H,m), 1.15-1.00 (15H, m).

Example 36N-({6-{[2,2-Bis(4-chlorophenyl)ethyl]amino}-9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-9H-purin-2-yl}methyl)-N′-[2-(diisopropylamino)ethyl]urea

[0287]

[0288](2R,3R,4S,5R)-2-(2-(Aminomethyl)-6-{[2,2-bis(4-chlorophenyl)ethyl]amino}-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol(0.1 g, 0.18 mmol) (Preparation 63) was dissolved in a mixture ofisopropanol (0.5 ml) and Genklene (Trade Mark) (5 ml).N-[2-(Diisopropylamino)ethyl]-1H-imidazole-1-carboxamide (48 mg, 0.20mmol) (Preparation 27) was added and the reaction mixture was heatedunder reflux for 2 hours. MoreN-[2-(diisopropylamino)ethyl]-1H-imidazole-1-carboxamide (35 mg, 0.15mmol) (Preparation 27) was then added and the reaction mixture washeated under reflux for a further 2 hours. The reaction mixture was thenallowed to cool and the solvent was removed under reduced pressure. Theresidue was purified by flash chromatography on silica gel eluting withdichloromethane:methanol:0.88 concentrated aqueous ammonia (95:5:0.5 byvolume) increasing in polarity to dichloromethane:methanol:0.88concentrated aqueous ammonia (90:10:2 by volume) to give the titlecompound (0.09 g) as a gum.

[0289] m/z MH⁺ 715.

[0290] δ_(H) (400 MHz; CD₃OD): 8.10 (1H, s), 7.35-7.20 (8H, m),7.20-7.15 (1H, m), 5.90-5.85 (1H, m), 4.75-4.70 (1H, m), 4.55-4.45 (1H,m), 4.40-4.35 (2H, m), 4.35-4.15 (3H, m), 4.15-4.10 (1H, m), 3.90-3.80(1H, m), 3.70-3.65 (1H, m), 3.25-3.10 (2H, m), 1.20-1.00 (12H, m).

Example 37N-({6-{[2,2-Bis(4-methylphenyl)ethyl]amino}-9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-9H-purin-2-yl}methyl)-N′-[2-(diisopropylamino)ethyl]urea

[0291]

[0292] The title compound was prepared from(2R,3R,4S,5R)-2-(2-(aminomethyl)-6-{[2,2-bis(4-methylphenyl)ethyl]amino}-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol (Preparation 60) andN-[2-(diisopropylamino)ethyl]-1H-imidazole-1-carboxamide (Preparation27) using a similar procedure to that used in Example 36.

[0293] m/z MH⁺ 673.

[0294] δ_(H) (400 MHz; CD₃OD): 8.05 (1H, s), 7.20-7.15 (4H, m),7.05-7.00 (4H, m), 5.90-5.85 (1H, m), 4.75-4.70 (1H, m), 4.40-4.30 (3H,m), 4.30-4.25 (1H, m), 4.15-4.10 (1H, m), 3.90-3.80 (1H, m), 3.75-3.70(1H, m), 3.10-3.05 (2H, m), 3.05-2.90 (2H, m), 2.50-2.45 (2H, m), 2.05(6H, m), 1.00-0.95 (12H, m).

Example 38N-({6-{[2,2-Bis(3-chlorophenyl)ethyl]amino}-9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-9H-purin-2-yl}methyl)-N′-[2-(diisopropylamino)ethyl]urea

[0295]

[0296] The title compound was prepared from(2R,3R,4S,5R)-2-(2-(aminomethyl)-6-{[2,2-bis(4-methylphenyl)ethyl]amino}-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol (Preparation 62) andN-[2-(diisopropylamino)ethyl]-1H-imidazole-1carboxamide (Preparation 27)in a similar procedure to that used in Example 36.

[0297] m/z MH⁺ 715.

[0298] δ_(H) (400 MHz; CD₃OD): 8.10-8.05 (1H, m), 7.35-7.10 (8H, m),5.90-5.85 (1H, m), 4.75-4.70 (1H, m), 4.60-4.45 (1H, m), 4.40-4.15 (5H,m), 4.10-4.05 (1H, m), 3.85-3.80 (1H, m), 3.70-3.65 (1H, m), 3.15-3.00(4H, m), 2.65-2.50 (2H, m), 1.05-0.90 (1 2H, m).

Example 39N-({6-{[2,2-Bis(3-chlorophenyl)ethyl]amino}-9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-9H-purin-2-yl}methyl)-N′-[2-(diisopropylamino)ethyl]urea

[0299]

[0300] The title compound was prepared from(2R,3R,4S,5R)-2-(2-(aminomethyl)-6-{[2,2-bis(3-methylphenyl)ethyl]amino}-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol(Preparation 65) andN-[2-(diisopropylamino)ethyl]-1H-imidazole-1-carboxamide (Preparation27) using a similar procedure to that used in Example 36.

[0301] m/z MH⁺ 673.

[0302] δ_(H) (400 MHz; CD₃OD): 8.10 (1H, s), 7.20-7.05 (6H, m),5.90-5.85 (1H, m), 4.75-4.70 (1H, m), 4.40-4.25 (5H, m), 4.25-4.15 (2H,m), 4.15-4.10 (1H, m), 3.90-3.80 (1H, m), 3.70-3.65 (1H, m), 3.15-3.00(4H, m), 2.60-2.45 (2H, m), 2.05 (6H, s), 1.10-0.95 (12H, m).

Example 40(2S,3S,4R,5R)-5-{2-{[({[2-(Diisopropylamino)ethyl]amino}carbonyl)amino]methyl}-6-[(1-naphthylmethyl)amino]-9H-purin-9-yl}-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide

[0303]

[0304] The title compound was prepared from(2S,3S,4R,5R)-5-{2-(aminomethyl)-6-[(1-naphthylmethyl)amino]-9H-purin-9-yl}-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide(Preparation 69) andN-[2-(diisopropylamino)ethyl]-1H-imidazole-1-carboxamide (Preparation27) by similar procedure to that used in Example 3.

[0305] m/z MH⁺ 648.

[0306] δ_(H) (400 MHz; CD₃OD): 8.20 (1H, s), 8.15-8.10 (1H, m),7.90-7.85 (1H, m), 7.80-7.75 (1H, m), 7.55-7.50 (1H, m), 7.50-7.45 (1H,m), 7.45-7.40 (1H, m), 6.05-6.00 (1H, m), 5.35-5.25 (2H, m), 4.45-4.35(4H, m), 3.35-3.20 (2H, m), 3.10-3.00 (2H, m), 3.00-2.90 (2H, m),2.50-2.40 (2H, m), 1.10-1.05 (3H, m).

[0307] The following Preparations describe the preparation of certainintermediates used in the preceding Examples.

Preparation 1(2R,3R,4R,5R)-4-(Acetyloxy)-2-[(acetyloxy)methyl]-5-{2-cyano-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}tetrahydro-3-furanylacetate

[0308]

[0309] N,O-Bistrimethylsilylacetamide (44 ml, 0.18 mol) was added to asuspension of 6-[(2,2-diphenylethyl)amino]-9H-purine-2-carbonitrile(10.0 g, 0.03 mol) (Preparation 24) in 1,1,1-trichloroethane (250 ml).The suspension was heated under reflux. When all suspended solid haddissolved the reaction mixture was allowed to cool to room temperatureand the solvent was removed under reduced pressure. The residue wastwice dissolved in toluene (50 ml) and the solvent was removed underreduced pressure. The residue was then dissolved in toluene (100 ml) and(2R,3R,4R,5S)-4,5-bis(acetyloxy)-2-[(acetyloxy)methyl]tetrahydro-3-furanylacetate (10.3 g, 0.032 mol) was added. The solution was stirred at roomtemperature and trimethylsilyltrifluoromethanesulphonate (16 ml, 0.088mol) was carefully added. The resulting solution was heated under refluxfor 2 hours and then allowed to cool to room temperature. The reactionmixture was diluted by the addition of ethyl acetate (100 ml) and thenwashed with saturated aqueous sodium hydrogen carbonate solution (tenportions of 100 ml) and saturated aqueous sodium chloride solution (100ml). The aqueous extracts were combined and washed with ethyl acetate(three portions of 100 ml). The combined organic layers were dried(anhydrous magnesium sulphate) and the solvent was removed under reducedpressure to give a solid that was purified by column chromatography onsilica gel eluting with dichloromethane:methanol:0.88 concentratedaqueous ammonia (97:3:0.5 by volume increasing to 80:20:3 by volume).This gave the title compound as a foam (8.5 g).

[0310] δ_(H) (4 MHz; CDCl₃): 7.95 (1H, s), 7.35-7.20 (10H, m), 6.15-6.10(1H, m), 5.95-5.90 (1H, m), 5.80-5.75 (1H, m), 5.60-5.55 (1H, m),4.45-4.35 (4H, m), 4.35-4.25 (2H, m), 2.15 (3H, s), 2.10 (3H, s), 2.05(3H, s).

Preparation 2(2R,3R,4S,5R)-2-{2-(Aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(hydroxymethyl)tetrahydro-3,4-furandiol

[0311]

[0312] 10% Palladium on carbon (200 mg) was added to a solution of(2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-{2-cyano-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}tetrahydro-3-furanylacetate (Preparation 1) (1.9 g, 3.2 mmol) in a saturated solution ofammonia in ethanol (100 ml). The reaction mixture was stirred under anatmosphere of hydrogen (414 kPa, 60 psi) for 16 hours at roomtemperature. The solids were removed by filtration through Arbocel(Trade Mark) and the solvent was removed under reduced pressure. Theresidue was purified by column chromatography on silica gel eluting withdichloromethane:methanol 0.88 concentrated aqueous ammonia (90:10:1 byvolume increasing to 80:20:2 by volume). This gave the title compound asa solid (770 mg).

[0313] m/z: MH⁺ 477.

[0314] δ_(H) (4 MHz; CDCl₃): 8.10 (1H, s), 7.35-7.20 (8H, m), 5.90-5.85(1H, m), 4.75-4.70 (1H, m), 4.50-4.40 (1H, m), 4.30-4.20 (2H, m), 4.10(1H, m), 3.90-3.80 (2H, m), 3.70-3.65 (1H, m).

Preparation 32-(Aminomethyl)-N-(2,2-diphenylethyl)-9-tetrahydro-2H-pyran-2-yl-9H-purin-6-amine

[0315]

[0316]6-[(2,2-Diphenylethyl)amino]-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-2-carbonitrile(19.7 g, 0.046 mol) (Preparation 23) was dissolved in a saturatedsolution of ammonia in ethanol (500 ml). 10% Palladium on carbon (2 g)was added and the suspension was stirred under an atmosphere of hydrogen(414 kPa, 60 psi) for 36 hours. The suspension was filtered throughArbocel (Trade Mark) and the solvent was removed under reduced pressure.This gave the title compound as a foam (17.7 g).

[0317] δ_(H) (4 MHz; CDCl₃): 7.84 (1H, s), 7.36-7.14 (10H, m), 5.70 (1H,d), 5.60 (1H, br s), 4.42-4.20 (3H, m), 4.14 (1H, d), 3.95 (2H, s), 3.78(1H, t), 2.20-1.90 (5H, m), 1.88-1.50 (3H, m).

Preparation 4N-({6-[(2,2-Diphenylethyl)amino]-9-tetrahydro-2H-pyran-2-yl-9H-purin-2-yl}methyl)-N′-[2-(1-piperidinyl)ethyl]urea

[0318]

[0319] 2-(1-Piperidinyl)ethanamine (0.35mi, 2.46 mmol) was added to asolution of N,N′-carbonyldiimidazole (420 mg, 2.6 mmol) indichloromethane (100 ml). The reaction mixture was stirred for tenminutes at room temperature and then2-(aminomethyl)-N-(2,2-diphenylethyl)-9-tetrahydro-2H-pyran-2-yl-9H-purin-6-amine(1.0 g, 2.33 mmol) (Preparation 3) was added. The reaction mixture wasthen stirred for 3 hours at room temperature. Dichloromethane (50 ml)was then added and the resulting solution was washed with water (50 ml)and saturated aqueous sodium chloride solution (50 ml). The organiclayer was dried with anhydrous magnesium sulphate and the solvent wasremoved under reduced pressure. The residue was purified by columnchromatography on silica gel eluting with dichloromethane:methanol:0.88concentrated aqueous ammonia (93:7:1 by volume). This gave the titlecompound as an oil (300 mg).

[0320] m/z: MH⁺ 583.

[0321] δ_(H) (400 MHz; CDCl₃): 7.85 (1H, s), 7.55 (1H, s), 7.30-7.05(10H, m), 5.70-5.60 (1H, m), 4.50-4.00 (6H, m), 3.75-3.60 (1H, m),3.30-3.10 (2H, m), 2.45-2.20 (6H, m), 2.05-1.85 (2H, m), 1.85-1.25 (10H,m).

Preparation 5N-({6-[(2,2-Diphenylethyl)amino]-9H-purin-2-yl}methyl)-N′-[2-(1-piperidinyl)ethyl]urea

[0322]

[0323] A solution ofN-({6-[(2,2-diphenylethyl)amino]-9-tetrahydro-2H-pyran-2-yl-9H-purin-2-yl}methyl)-N′-[2-(1-piperidinyl)ethyl]urea(300 mg, 0.51 mmol) (Preparation 4) in methanol (150 ml) was treatedwith aqueous hydrochloric acid (2M, 100 ml). The reaction mixture wasstirred at room temperature for 2 hours. The solvent volume was thenreduced to 100 ml by evaporation under reduced pressure. Saturatedaqueous sodium hydrogen carbonate solution (50 ml) and ethyl acetate(200 ml) were added. The two phases were separated. The organic layerwas washed with saturated aqueous sodium chloride solution (100 ml),dried (anhydrous magnesium sulphate) and evaporated to give the titlecompound as a solid (255 mg).

[0324] m/z: MH⁺ 499.

[0325] δ_(H) (400 MHz; CDCl₃): 7.80 (1H, s), 7.35-7.10 (10H, m),4.55-4.10 (5H, m), 3.40-3.20 (2H, m), 2.60-2.30 (6H, m), 1.60-1.25 (6H,m).

Preparation 6(2R,3R,4R,5R)-4-(Acetyloxy)-2-[(acetyloxy)methyl]-5-(6-[(2,2-diphenylethyl)amino]-2-{[({[2-(1-piperidinyl)ethyl]amino}carbonyl)amino]methyl}-9H-purin-9-yl)tetrahydro-3-furanylacetate

[0326]

[0327] N,O-Bistrimethylsilylacetamide (0.34 ml, 1.4 mmol) was added to astirred suspension ofN-({6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl)-N′-[2-(1-piperidinyl)ethyl]urea(100 mg, 0.2 mmol) (Preparation 5) in 1,1,1-trichloroethane (20 ml) at50° C. The reaction mixture was stirred at this temperature for 30minutes, allowed to cool to room temperature and then evaporated underreduced pressure. Toluene (5 ml) was added and the solvent was removedunder reduced pressure. The residue was redissolved in toluene (20 ml)and(2R,3R,4R,5S)-4,5-bis(acetyloxy)-2-[(acetyloxy)methyl]tetrahydro-3-furanylacetate (0.064 g, 0.2 mmol) and thentrimethylsilyltrifluoromethanesulphonate (0.1 ml, 0.35 mmol) were added.The reaction mixture was then heated under reflux for 2 hours. Thereaction was allowed to cool to room temperature and diluted with ethylacetate (100 ml). The solution was washed with saturated aqueous sodiumhydrogen carbonate solution (50 ml) and saturated aqueous sodiumchloride solution (50 ml) and then dried over anhydrous magnesiumsulphate. The solvent was removed to give a residue that was purified bycolumn chromatography on silica gel eluting withdichloromethane:methanol:0.88 concentrated aqueous ammonia (90:10:1 byvolume) to give the title compound as an oil (100 mg).

[0328] m/z: MH⁺ 757.

[0329] δ_(H) (400 MHz; CDCl₃): 7.65 (1H, s), 7.35-7.15 (1 OH, m),6.05-6.00 (1H, m), 6.00-5.90 (2H, m), 5.85-5.75 (1H, m), 5.45-5.40 (1H,m), 4.60-4.15 (7H, m), 3.35-3.25 (2H, m), 2.50-2.35 (6H, m), 2.15 (3H,s), 2.10 (3H, s), 1.90 (3H, s), 1.60-1.35 (6H, m).

Preparation 7(2S,3S,4R,5R)-4-(Benzoyloxy)-5-{2-cyano-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-2-[(ethylamino)carbonyl]tetrahydro-3-furanylbenzoate

[0330]

[0331] A mixture of6-[(2,2-diphenylethyl)amino]-9H-purine-2-carbonitrile (Preparation 24)(5.00 g, 14.7 mmol),(2S,3S,4R,5R)-5-(acetyloxy)-4-(benzoyloxy)-2-[(ethylamino)carbonyl]tetrahydro-3-furanylbenzoate and(2S,3S,4R,5S)-5-(acetyloxy)-4-(benzoyloxy)-2-[(ethylamino)carbonyl]tetrahydro-3-furanylbenzoate (Preparation 18) (6.50 g, 14.7 mmol) and iodine (0.38 g, 15.0mmol) were heated together at 150° C. under reduced pressure (7 kPa, 1psi) for 2.5 hours. The reaction was then allowed to stand at roomtemperature for 18 hours. The residue was purified by columnchromatography on silica gel eluting with a gradient system of ethylacetate: pentane (40:60 by volume) increasing in polarity to neat ethylacetate to afford the title compound as a foam (4.95 g).

[0332] δ_(H) (400 MHz; CDCl₃): 8.12 (3H, m), 7.79 (3H, m), 7.63 (1H, m),7.50 (3H, m), 7.38-7.16 (11H, m), 6.35 (2H, m), 6.10 (1H, t), 6.03 (1H,d), 4.94 (1H, m), 4.35 (3H, m), 3.57 (2H, m), 1.30 (3H, t).

Preparation 8(2S,3S,4R,5R)-5-{2-Cyano-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide

[0333]

[0334] A solution of(2S,3S,4R,5R)-4-(benzoyloxy)-5-{2-cyano-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-2-[(ethylamino)carbonyl]tetrahydro-3-furanylbenzoate (Preparation 7) (4.75 g, 6.59 mmol) in ethanol (200 ml) wassaturated with ammonia gas and stirred at room temperature for 18 hours.The solvent was removed under reduced pressure and the residue waspurified by column chromatography on silica gel eluting with a gradientsystem of dichloromethane:methanol (95:5 by volume) gradually changingto dichloromethane:methanol (90:10 by volume) to afford the titlecompound as a solid (2.80 g).

[0335] δ_(H) (400 MHz; d₆DMSO): 8.65 (1H, s), 8.54 (1H, br t), 8.18 (1H,br m), 7.13-7.42 (10H, m), 5.98 (1H, m), 5.65 (1H, m), 5.57 (1H, m),4.59 (2H, m), 4.32 (1H, m), 4.08-4.28 (3H, m), 3.20 (2H, m), 1.05 (3H,t).

Preparation 92-Chloro-N—(1-naphthylmethyl)-9-tetrahydro-2H-pyran-2-yl-9H-purin-6-amine

[0336]

[0337] 1-Naphthylmethanamine (5.4 g, 19.7 mmol) was added to a stirredsolution of 2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (3.5 g,22.3 mmol) (Preparation 19) and triethylamine (4 g, 39.6 mmol) inacetonitrile (150 ml) at room temperature. The reaction mixture wasstirred at room temperature for 64 hours. The solvent was removed underreduced pressure, ethyl acetate (100 ml) was added and then the solventwas removed under reduced pressure again. The residue was purified bycolumn chromatography on silica gel eluting with pentane: ethyl acetate(1:1 by volume) increasing in polarity to neat ethyl acetate. Thesolvent was removed under reduced pressure to give the title compound(7.56 g) as a solid.

[0338] δ_(H) (400 MHz; CDCl₃): 8.10-8.00 (1H, m), 7.90-7.80 (3H, m),7.55-7.45 (3H, m), 7.45-7.40 (1H, m), 6.15 (1H, s), 5.70-5.60 (1H, m),5.25 (1H, bs), 4.20-4.10 (1H, m), 3.80-3.70 (1H, m), 2.15-2.00 (2H, m),2.00-1.80 (1H, m), 1.80-1.60 (3H, m).

Preparation 10 6-[(1-Naphthylmethyl)amino]-9H-purine-2-carbonitrile

[0339]

[0340] Tetrakistriphenylphosphine palladium (1.1 g, 0.95 mmol) was addedto a solution of2-chloro-N-(1-naphthylmethyl)-9-tetrahydro-2H-pyran-2-yl-9H-purin-6-amine(7.5 g, 19 mmol) (Preparation 9), zinc cyanide (1.4 g, 11.9 mmol) andN-ethyl-N-isopropyl-2-propanamine (4 ml, 23 mmol) inN′N′-dimethylformamide (80 ml). The reaction mixture was heated to 100°C. for 16 hours. The reaction mixture was allowed to cool to roomtemperature and ethyl acetate (250 ml) was added. The resulting mixturewas extracted with aqueous sodium hydroxide solution (2M, 100 ml). Thesodium hydroxide layer was extracted with more ethyl acetate (50 ml).The ethyl acetate layers were combined and washed with water (50 ml) andthen dried over anhydrous magnesium sulphate. The solvent was removedunder reduced pressure, the residue was dissolved in dichloromethane(100 ml) and the solvent was removed under reduced pressure again. Theresidue was purified by column chromatography on silica gel eluting withdichloromethane:methanol (99:2 by volume) increasing in polarity todichloromethane:methanol (90:10 by volume). The solvent was removedunder reduced pressure to give the title compound (1.8 g) as a foam. Themajor product of this reaction was actually6-[(1-naphthylmethyl)amino]-9-tetrahydro-2H-pyran-2-yl-9H-purine-2-carbonitrile(2.7 g).

[0341] δ_(H) (400 MHz; d₆DMSO): 8.35-8.25 (1H, m), 8.25-8.15 (1H, m),7.95-7.90 (1H, m), 7.90-7.80 (1H, m), 7.60-7.40 (4H, m), 5.20-5.10 (2H,m).

Preparation 11(2S,3S,4R,5R)-5-{2-(Aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide

[0342]

[0343] 10% Palladium on carbon (400 mg) was added to a solution of(2S,3S,4R,5R)-4-(benzoyloxy)-5-{2-cyano-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-2-[(ethylamino)carbonyl]tetrahydro-3-furanylbenzoate (Preparation 7) (2.0 g, 2.70 mmol) in a saturated solution ofammonia in ethanol (40 ml). The reaction mixture was stirred under anatmosphere of hydrogen (414 kPa, 60 psi) for 16 hours at roomtemperature. The suspension was filtered through Arbocel (Trade Mark)and the solvent was removed under reduced pressure. The residue waspurified by column chromatography on silica gel eluting withdichloromethane:methanol:0.88 concentrated aqueous ammonia (95:5:0.5 byvolume) increasing to (90:10:1 by volume). This gave the title compoundas a solid (1.2 g).

[0344] δ_(H) (400 MHz; d₆DMSO): 8.55 (1H, s), 8.45-8.30 (1H, br s),7.45-7.10 (10H, m), 6.10-6.00 (1H, m), 4.70-4.50 (2H, m), 4.35-4.10 (6H,m), 3.20-3.05 (2H, m), 1.10-0.95 (3H, m).

Preparation 12(2S,3S,4R,5R)-5-(6-[(2,2-Diphenylethyl)amino]-2-{[({[2-(isopropylamino)ethyl]amino}carbonyl)amino]methyl}-9H-purin-9-yl)-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide

[0345]

[0346] NN′-Carbonyldiimidazole (0.47 g, 2.9 mmol) was added to a stirredsolution of(2S,3S,4R,5R)-5-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide(1.5 g, 2.9 mmol) (Preparation 11) in NN′-dimethylformamide (10 ml) atroom temperature. The reaction mixture was stirred at room temperaturefor 4 hours. N′-Isopropylethylene diamine was then added and thereaction mixture was stirred for 16 hours at room temperature. Thesolvent was then removed under reduced pressure. The residue waspurified by column chromatography on silica gel eluting withdichloromethane:methanol:0.88 concentrated aqueous ammonia (95:5:0.5 byvolume) increasing in polarity to dichloromethane:methanol:0.88concentrated aqueous ammonia (80:20:3 by volume). This gave the titlecompound as a foam (0.66 g).

[0347] m/z MH⁺ 647.

[0348] δ_(H) (400 MHz; CD₃OD): 8.20 (1H, m), 7.35-7.20 (8H, m),7.20-7.10 (2H, m), 6.05-6.00 (1H, m), 4.55-4.40 (5H, m), 4.30-4.20 (2H,m), 3.35-3.20 (4H, m), 2.90-2.80 (1H, m), 2.70-2.65 (2H, m), 1.15-1.05(6H, m).

Preparation 13(2R,3R,4S,5R)-2-{2-(Aminomethyl)-6-[(9H-fluoren-9-ylmethyl)amino]-9H-purin-9-yl}-5-(hydroxymethyl)tetrahydro-3,4-furandiol

[0349]

[0350] Ammonia gas was passed through an ice cold solution of(2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-{2-cyano-6-[(9H-fluoren-9-ylmethyl)amino]-9H-purin-9-yl}tetrahydro-3-furanylacetate (1.2 g, 2 mmol) (Preparation 71) in ethanol (40 ml) until thesolution was saturated. 10% Palladium on carbon (120 mg) was added andthe reaction mixture was stirred under an atmosphere of hydrogen gas(413.7 kPa, 60 psi) at room temperature for 40 hours. The suspension wasfiltered through Arbocel (Trade Mark) and the solvent was removed fromthe filtrate under reduced pressure. The residue was purified by columnchromatography on silica gel eluting with dichloromethane:methanol:0.88concentrated aqueous ammonia (96:4:0.4 by volume) increasing in polarityto dichloromethane:methanol:0.88 concentrated aqueous ammonia (94:6:0.5by volume). The solvent was removed under reduced pressure to give thetitle compound (358 mg) as a foam.

[0351] m/z MH⁺ 475.

[0352] δ_(H) (400 MHz; CD₃OD): 8.20 (1H, m), 7.85-7.75 (2H, m),7.70-7.60 (2H, m), 7.40-7.20 (4H, m), 6.00-5.90 (1H, m), 4.40-4.35 (1H,m), 4.35-4.30 (1H, m), 4.20-4.00 (3H, m), 3.90-3.70 (4H, m).

Preparation 14(2S,3S,4R,5R)-4-(Benzoyloxy)-5-(6-[(2,2-diphenylethyl)amino]-2-{[({[2-(1-piperidinyl)ethyl]amino}carbonyl)amino]methyl}-9H-Purin-9-yl)-2-[(ethylamino)carbonyl]tetrahydro-3-furanylbenzoate

[0353]

[0354] N,O-Bistrimethylsilylacetamide (0.34 ml, 1.4 mmol) was added to astirred suspension ofN-({6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl)-N′-[2-(1-piperidinyl)ethyl]urea(100 mg, 0.2 mmol) (Preparation 5) in 1,1,1-trichloroethane (20 ml) at50° C. The reaction mixture was stirred at this temperature for 30minutes, allowed to cool to room temperature and then evaporated underreduced pressure. Toluene (5 ml) was added and the solvent was removedunder reduced pressure. The residue was redissolved in toluene (20 ml).(2S,3S,4R,5R)-5-(Acetyloxy)-4-(benzoyloxy)-2-[(ethylamino)carbonyl]tetrahydro-3-furanylbenzoate and(2S,3S,4R,5S)-5-(acetyloxy)-4-(benzoyloxy)-2-[(ethylamino)carbonyl]tetrahydro-3-furanylbenzoate (Preparation 18) and thentrimethylsilyltrifluoromethanesulphonate (0.1 ml, 0.35 mmol) were addedand the reaction mixture was heated under reflux for 2 hours. Thereaction was then allowed to cool to room temperature and diluted withethyl acetate (100 ml). The solution was washed with saturated aqueoussodium hydrogen carbonate solution (2×50 ml) and saturated aqueoussodium chloride solution (50 ml) and then dried (anhydrous magnesiumsulphate). The solvent was removed to give a residue that was purifiedby column chromatography on silica gel eluting withdichloromethane:methanol:0.88 concentrated aqueous ammonia (95:5:0.5 byvolume). This gave an impure oil (100 mg) which was used without furtherpurification in subsequent experiments.

Preparation 15(3aR,4S,6R,6aR)-N-Ethyl-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide

[0355]

[0356] Oxalyl chloride (14.0 ml, 160 mmol) was added dropwise to astirred solution of(3aR,4S,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxylicacid (J. Am. Chem. Soc., 80, 1958, 5168-5173) (23.30 g, 107 mmol) inanhydrous dichloromethane (120 ml) and N,N′-dimethylformamide (2 drops)and the mixture was stirred at room temperature for 3 hours until gasevolution had ceased. TLC analysis showed that some starting materialstill remained and so more N,N-dimethylformamide (2 drops) was added andstirring was continued for 1 hour. The solvent was removed under reducedpressure and the residue was azeotroped twice with anhydrousdichloromethane. The residue was then dissolved in anhydrousdichloromethane (200 ml) and the solution was treated dropwise with asolution of ethylamine in tetrahydrofuran (2M, 140 ml, 280 mmol). Thissolution was left to stand at room temperature for 48 hours. Diethylether (250 ml) was added and the mixture was stirred for 15 minutes. Themixture was filtered and the solvent was removed from the filtrate underreduced pressure. The residue was purified by column chromatography onsilica gel eluting with a gradient system of dichloromethane ethylacetate (100:0 by volume) gradually changing to dichloromethane:ethylacetate (44: 66 by volume) to afford the title compound as a yellowsolid (24.70 g).

[0357] δ_(H) (400 MHz; CDCl₃): 6.53 (1H, br m), 5.12 (1H, dd), 5.07 (1H,d), 4.60 (1H, d), 4.54 (1H, dd), 3.46 (3H, s), 3.32 (2H, m), 1.51 (3H,s), 1.34 (3H, s), 1.15 (3H, t).

[0358] m/z MH⁺ 246.

Preparation 16(2S,3S,4R,5R)-N-Ethyl-3,4-dihydroxy-5-methoxytetrahydro-2-furancarboxamideand(2S,3S,4R,5S)-N-ethyl-3,4-dihydroxy-5-methoxytetrahydro-2-furancarboxamide

[0359]

[0360] A solution of(3aR,4S,6R,6aR)-N-ethyl-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide(Preparation 15) (24.60 g, 100 mmol) and pyridinium p-toluenesulphonate(2.50 g, 10 mmol) in methanol (500 ml) was heated under reflux for 18hours. NMR analysis showed that some starting material still remainedand therefore the solvent was removed under reduced pressure. Theresidue was dissolved in methanol (500 ml) and heated under reflux for 8hours. NMR analysis showed that some starting material still remainedtherefore the solvent was removed under reduced pressure once more, theresidue was dissolved in methanol (500 ml) and the resulting solutionwas heated under reflux for 24 hours. The solvent was then removed underreduced pressure and the residue was azeotroped three times withdichloromethane to afford the title compound as an oil and as a mixtureof α and β anomers (20.50 g).

[0361] δ_(H) (400 MHz; CDCl₃): 6.58 (1H, br m), 4.99 (0.25H, d), 4.94(0.75H, d), 4.46 (0.25H, d), 4.37 (1H, m), 4.24 (0.25H, dd), 4.05 (1H,m), 3.52 (0.75H, s), 3.47 (2.25H, s), 3.30 (2H, m), 1.16 (3H, m).

Preparation 17(2S,3S,4R,5R)-4-(Benzoyloxy)-2-[(ethylamino)carbonyl]-5-methoxytetrahydro-3-furanylbenzoate and(2S,3S,4R,5S)-4-(benzoyloxy)-2-[(ethylamino)carbonyl]-5-methoxytetrahydro-3-furanylbenzoate

[0362]

[0363] A solution of benzoyl chloride (30.0 ml, 259 mmol) indichloromethane (100 ml) was added slowly to a solution of(2S,3S,4R,5R)-N-ethyl-3,4-dihydroxy-5-methoxytetrahydro-2-furancarboxamideand(2S,3S,4R,5S)-N-ethyl-3,4-dihydroxy-5-methoxytetrahydro-2-furancarboxamide(Preparation 16) (20.50 g, 100 mmol) and pyridine (33.0 ml, 409 mmol) indichloromethane (400 ml) and the resulting mixture was stirred at roomtemperature for 18 hours. The solvent was removed under reduced pressureand the residue was partitioned between diethyl ether and aqueoushydrochloric acid (1 M, 300 ml). The layers were separated and theaqueous layer was re-extracted with diethyl ether. The organic layerswere combined, washed sequentially with water and brine, dried overanhydrous magnesium sulphate, filtered and evaporated under reducedpressure. The residue was purified by column chromatography on silicagel eluting with a gradient system of dichloromethane:diethyl ether(95:5 by volume) gradually changing to dichloromethane:diethyl ether(80:20 by volume) to afford the title compound as an oil and as amixture of α and β anomers (37.0 g).

[0364] δ_(H) (400 MHz; CDCl₃): 8.16 (0.5H, d), 7.95 (1.5H, d), 7.88(1.5H, d), 7.81 (0.5H, d), 7.25-7.66 (6H, m), 6.65 (1H, br m), 5.88 (1H,m), 5.60 (0.75H, dd), 5.46 (0.25H, d), 5.23 (0.75H, d), 5.17 (0.25H, t),4.80 (1H, m), 3.59 (2.25H, s), 3.49 (0.75H, s), 3.39 (2H, m), 1.23 (3H,t).

Preparation 18(2S,3S,4R,5R)-5-(Acetyloxy)-4-(benzoyloxy)-2-[(ethylamino)carbonyl]tetrahydro-3-furanylbenzoate and(2S,3S,4R,5S)-5-(acetyloxy)-4-(benzoyloxy)-2-[(ethylamino)carbonyl]tetrahydro-3-furanylbenzoate

[0365]

[0366] A solution of(2S,3S,4R,5R)-4-(benzoyloxy)-2-[(ethylamino)carbonyl]-5-methoxytetrahydro-3-furanylbenzoate and(2S,3S,4R,5S)-4-(benzoyloxy)-2-[(ethylamino)carbonyl]-5-methoxytetrahydro-3-furanylbenzoate (Preparation 17) (37.0 g, 89.6 mmol) in a mixture of aceticacid (330 ml, 5.77 mol) and acetic anhydride (67 ml, 709 mmol) wascooled to −10° C. and treated dropwise with hydrochloric acid (12 N, 7.0ml, 132 mmol). The mixture was stirred for 18 hours, during which timeit was allowed to warm to room temperature. After cooling the mixture to0° C., water (1000 ml) was added slowly. The mixture was then extractedthree times with ethyl acetate (3 portions of 500 ml). The organiclayers were combined, washed sequentially with water, a saturatedaqueous solution of sodium hydrogen carbonate and brine, dried overanhydrous magnesium sulphate, filtered and evaporated under reducedpressure. The residue was purified by column chromatography on silicagel eluting with a gradient system of diethyl ether:pentane (66:44 byvolume) gradually changing to diethyl ether:pentane (100:0 by volume).The residue was further purified by column chromatography on silica geleluting with a gradient system of dichloromethane:diethyl ether (95:5 byvolume) gradually changing to dichloromethane:diethyl ether (90:10 byvolume) to afford the title compound as a mixture of α- and β-anomers(15.40 g).

[0367] δ_(H) (400 MHz; CDCl₃): 8.12 (0.8H, d), 7.97 (1.2H, d), 7.92(1.2H, d), 7.79 (0.8H, d), 7.24-7.65 (6H, m), 6.73 (0.4H, d), 6.62(0.4H, br m), 6.46 (0.6H, br m), 6.42 (0.6H, d), 6.07 (0.4H, dd), 5.95(0.6H, t), 5.72 (0.6H, d), 5.44 (0.4H, t), 4.94 (0.4H, d), 4.86 (0.6H,d), 3.36 (2H, m), 2.17 (1.8H, s), 2.10 (1.2H, s), 1.20 (3H, m).

Preparation 19 2,6-Dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine

[0368]

[0369] 2,6-Dichloro-9H-purine (20 g, 0.11 mol) and 4-toluenesulphonicacid monohydrate (0.2 g) were dissolved in ethyl acetate (300 ml), themixture was heated to 50° C. and a solution of 3,4-dihydro-2H-pyran(12.6 ml, 0.14 mol) in ethyl acetate (50 ml) was added slowly over 30minutes. The reaction mixture was cooled to room temperature, water (100ml) was added and the pH of the solution was adjusted to 7 by additionof a saturated aqueous solution of sodium hydrogen carbonate. Theorganic layer was separated, washed sequentially with water and brine,dried over anhydrous magnesium sulphate, filtered and evaporated underreduced pressure. The residue was azeotroped with pentane (100 ml) toafford the title compound as a slightly impure white solid (30.9 g).

[0370] δ_(H) (400 MHz; CDCl₃): 8.30 (1H, s), 5.75 (1H, dd), 4.25-4.15(1H, m), 3.85-3.70 (1H, m), 2.20-1.60 (6H, m).

Preparation 202-Chloro-N-(2,2-diphenylethyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine

[0371]

[0372] A solution of 2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine(Preparation 19) (30.9 g, 0.11 mol) in isopropyl alcohol (600 ml) wastreated with N-ethyl-N-isopropyl-2-propanamine (47.5 ml, 0.27 mol) and2,2-diphenylethylamine (24.8 g, 0.13 mol) and the resulting mixture washeated under reflux for 3 hours. The solvent was removed under reducedpressure and the residue was azeotroped with ethyl acetate. The residuewas purified by column chromatography on silica gel eluting with agradient system of ethyl acetate: hexane (40:60, by volume) graduallychanging to ethyl acetate:hexane (60:40, by volume) to afford the titlecompound as a foam (49.7 g).

[0373] δ_(H) (400 MHz; CDCl₃): 7.95-7.75 (1H, br s), 7.35-7.15 (10H, m),5.80-5.70 (1H, brs), 5.65(1H,d), 4.35(1H,m), 4.30-4.18(1H,brs),4.10(1H,d), 3.70(1H,t), 2.05-1.95 (2H, m), 1.95-1.80 (1H, m), 1.80-1.55(3H, m).

Preparation 21N-(2,2-Diphenylethyl)-2-(methylsulfanyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine

[0374]

[0375] A solution of2-chloro-N-(2,2-diphenylethyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine(Preparation 20) (49.7 g, 0.11 mol) in dry N,N-dimethylformamide (200ml) was treated with sodium thiomethoxide (10 g, 0.14 mol) and theresulting mixture was heated under an atmosphere of nitrogen at 100° C.for 90 minutes. The mixture was stirred at room temperature for 72 hoursand then reheated at 100° C. for a further 2 hours. The reaction mixturewas cooled and diluted with water (1000 ml). A suspension was formedwhich was extracted twice with diethyl ether (500 ml). The combinedorganic layers were washed sequentially with water and brine, dried overanhydrous magnesium sulphate, filtered and evaporated under reducedpressure. The residue was azeotroped sequentially with diethyl ether andpentane to afford the title compound as a foam (48.9 g).

[0376] δ_(H) (400 MHz; CDCl₃): 7.80 (1H, s), 7.20-7.10 (10H, m),5.70-5.55 (2H, d), 4.40-4.20 (3H, m), 4.20-4.05 (1H, m), 3.80-3.65 (1H,m), 2.60 (3H, s), 2.15-1.90 (3H, m), 1.90-1.60 (3H, m).

Preparation 22N-(2,2-Diphenylethyl)-2-(methylsulfonyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine

[0377]

[0378] A solution of Oxone (Trade Mark) (potassium peroxymonosulphate)(44 g, 71.7 mmol) in water (200 ml) was added dropwise over 2 hours to asolution ofN-(2,2-diphenylethyl)-2-(methylsulfanyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine(Preparation 21) (25 g, 56.2 mmol) and sodium hydrogencarbonate (20 g,238 mmol) in a mixture of acetone (1000 ml) and water (250 ml). Theresultant mixture was stirred at room temperature for 24 hours andfiltered and the residue was washed with acetone. The acetone wasremoved from the filtrate under reduced pressure and the resultingaqueous residue was extracted with ethyl acetate and thendichloromethane. The combined organic layers were washed with brine,dried over anhydrous magnesium sulphate, filtered and evaporated underreduced pressure. The residue was triturated with diethyl ether,filtered, washed with diethyl ether and pentane and then dried to affordthe title compound as a white solid (20.32 g).

[0379] δ_(H) (400 MHz; CDCl₃): 8.00 (1H, s), 7.35-7.15 (10H, m),6.05-5.95 (1H, br s), 5.75 (1H, d), 4.40-4.35 (1H, m), 4.35-4.20 (2H, brs), 4.15-4.05 (1H, m), 3.75 (1H, t), 3.30 (3H, s), 2.18-2.05 (1H, m),2.05-1.98 (1H, m), 1.98-1.80 (1H, m), 1.80-1.60 (3H, m).

Preparation 236-[(2,2-Diphenylethyl)amino]-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-2-carbonitrile

[0380]

[0381] A solution ofN-(2,2-diphenylethyl)-2-(methylsulfonyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine(Preparation 22) (20.1 g, 42.1 mmol) in dry N,N-dimethylformamide (100ml) was treated with potassium cyanide (5.5 g, 84.6 mmol) and themixture was heated at 120° C. for 24 hours under a nitrogen atmosphere.The mixture was cooled to room temperature and diluted with water (1000ml) and stirring was continued for a further 1 hour. The resultant solidwas filtered off and washed several times with water. The solid was thendissolved in dichloromethane and the solution was washed with water,dried over anhydrous magnesium sulphate, filtered and evaporated underreduced pressure. The residue was azeotroped with diethyl ether (twice)to afford the title compound as an oil (17 g).

[0382] δ_(H) (400 MHz; CDCl₃): 8.00 (1H, s), 7.40-7.20 (1 OH, m),6.00-5.75 (1H, br s), 5.70 (1H, d), 4.40-4.20 (3H, m), 4.20-4.10 (1H,m), 3.80-3.70 (1H, m), 2.20-1.90 (3H, m), 1.90-1.60 (3H, m).

Preparation 24 6-[(2,2-Diphenylethyl)amino]-9H-purine-2-carbonitrile

[0383]

[0384] A solution of6-[(2,2-diphenylethyl)amino]-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-2-carbonitrile(Preparation 23) (17 g, 40.1 mmol) in ethanol (850 ml) was treated with2 N aqueous hydrochloric acid (50 ml) and the mixture was stirred atroom temperature for 24 hours. The solvent was removed under reducedpressure, the residue was dissolved in ethanol and the solvent was againremoved under reduced pressure. The residue was triturated with diethylether, filtered, washed with diethyl ether and pentane and dried toafford the title compound as a solid (13.6 g).

[0385] δ_(H) (400 MHz; d₆DMSO): 8.30 (1H, s), 8.20-8.05 (1H, brs),7.40-7.10 (10H, m), 4.60-4.40 (1.4H, m), 4.20-4.00 (1.6H, m).

[0386] m/z [MH⁺] 341.

Preparation 25N′-({6-[(2,2-diphenylethyl)amino]-9-tetrahydro-2H-pyran-2-yl-9H-purin-2-yl}methyl)-N-methyl-N-[2-(2-pyridinyl)ethyl]urea

[0387]

[0388] N′N′-Carbonyldiimidazole (0.42 g, 2.6 mmol) was added to asolution of2-(aminomethyl)-N-(2,2-diphenylethyl)-9-tetrahydro-2H-pyran-2-yl-9H-purin-6-amine(1.0 g, 2.3 mmol) (Preparation 3) in dichloromethane (100 ml). Thereaction mixture was stirred for 16 hours at room temperature.Dichloromethane (100 ml) was added and the solution was washed withwater (50 ml) and saturated aqueous sodium chloride solution (50 ml).The organic layer was dried over anhydrous magnesium sulphate and thesolvent was removed under reduced pressure. A portion of this residue(200 mg) was dissolved in tetrahydrofuran (50 ml) andN-methyl-2-(2-pyridinyl)ethanamine (200 mg, 1.5 mmol) and triethylamine(0.14 ml, 1.0 mmol) were added. The reaction mixture was heated underreflux for 2.5 hours. The reaction mixture was allowed to cool to roomtemperature and the solvent was removed under reduced pressure. Theresidue was redissolved in ethylacetate (100 ml) and Washed with water(100 ml) and saturated aqueous sodium chloride solution (100 ml). Theorganic phase was dried over anhydrous magnesium sulphate and thesolvent was removed under reduced pressure. The residue was purified bycolumn chromatography on silica gel eluting withdichloromethane:methanol:0.88 concentrated aqueous ammonia (97:3:0.5 byvolume). The solvent was removed under reduced pressure to give thetitle compound as a foam (100 mg).

[0389] δ_(H) (400 MHz; CDCl₃): 8.50-8.40 (1H, m), 7.85-7.75 (1H, m),7.60-7.50 (1H, m), 7.30-7.10 (11H, m), 7.10-7.00 (1H, m), 6.20-6.10 (1H,m), 6.10-6.00 (1H, m), 5.70-5.60 (1H, m), 4.55-4.45 (2H, m), 4.35-4.15(3H, m), 4.15-4.05 (1H, m), 3.75-3.60 (3H, m), 3.05-2.95 (2H, m), 2.75(3H, s), 2.10-1.90 (3H, m), 1.80-1.50 (3H, m).

Preparation 26N′-({6-[(2,2-Diphenylethyl)amino]-9H-purin-2-yl}methyl)-N-methyl-N-[2-(2-pyridinyl)ethyl]urea

[0390]

[0391] Aqueous hydrochloric acid (2M, 5 ml) was added to a solution ofN′-({6-[(2,2-diphenylethyl)amino]-9-tetrahydro-2H-pyran-2-yl-9H-purin-2-yl}methyl)-N-methyl-N-[2-(2-pyridinyl)ethyl]urea(Preparation 25) in methanol (50 ml). The solution was stirred for 16hours at room temperature. The solvent was removed under reducedpressure. The residue was dissolved in ethyl acetate (100 ml) and thesolution was washed with saturated aqueous sodium hydrogen carbonatesolution (50 ml) and then dried over anhydrous magnesium sulphate. Thesolvent was removed under reduced pressure to give the title compound(0.161 g) as a gum.

[0392] δ_(H) (400 MHz; CD₃OD): 8.45-8.40 (1H, m), 7.90 (1H, m),7.70-7.65 (1H, m), 7.30-7.20 (10H, m), 7.15-7.10 (2H, m), 4.45-4.35 (3H,m), 4.30-4.20 (2H, m), 3.55-3.45 (2H, m), 2.95-2.90 (2H, m), 2.75 (3H,m).

Preparation 27 N-[2-(Diisopropylamino)ethyl]-1H-imidazole-1-carboxamide

[0393]

[0394] N′,N′-Diisopropyl-1,2-ethanediamine (1 g, 6.94 mmol) was added toa stirred solution of N,N′-carbonyidiimidazole (1.12 g, 6.94 mmol) indichloromethane (50 ml) at room temperature. The reaction mixture wasstirred for 1 hour and then diluted with more dichloromethane (50 ml),washed with water (60 ml), dried with anhydrous magnesium sulphate andevaporated under reduced pressure. This gave the title compound as asolid (600 mg).

[0395] δ_(H) (400 MHz; CDCl₃): 8.05 (1H, s), 7.25 (1H, s), 7.05 (1H, s),6.65 (1H, br s), 3.40-3.35 (2H, m), 3.10-3.00 (2H, m), 2.75-2.70 (2H,m), 1.05-1.00 (6H, m).

Preparations 28-37

[0396] The following compounds were prepared by the method ofPreparation 27 using the appropriate amine. Preparation Structure Number(starting materials) ¹H-NMR (400 MHz) 28

δ_(H) (400MHz; CDCl₃): 8.10 (1H, s), 7.35 (1H, s), 7.10 (1H, s), 6.80(1H, br s), 3.45 (2H, m), 2.55 (2H, m), 2.50-2.30 (4H, m), 1.60-1.40(6H, m). 29

δ_(H) (400MHz; CDCl₃): 8.10 (1H, s), 7.35 (1H, s), 7.10 (1H, s), 6.80(1H, br s), 3.45 (2H, m), 2.55 (2H, m), 2.50-2.30 (4H, m), 1.60-1.40(6H, m). 30

δ_(H) (400MHz; CDCl₃): 8.05 (1H, s), 7.50-7.45 (2H, m), 7.40 (1H, s),7.30-7.20 (3H, m), 7.15-7.10 (1H, m), 6.95 (1H, s), 3.30-3.25 (2H, m),2.90-2.85 (1H, m), 2.80-2.75 (2H, m), 1.35 (6H, m), 0.95-0.90 (6H, m).31

δ_(H) (400MHz; CDCl₃): 8.15 (1H, m), 8.05 (1H, s), 7.45 (1H, m), 7.20(1H, s), 7.00 (1H, s), 6.65 (1H, m), 6.55 (1H, m), 5.90 (1H, d), 4.25(2H, d), 4.05 (1H, m), 2.95 (2H, t), 2.10 (2H, d), 1.55 (2H, t). 32

δ_(H) (400MHz; CDCl₃): 8.05 (1H, s), 7.50-7.45 (2H, m), 7.40 (1H, s),7.30-7.20 (3H, m), 7.15-7.10 (1H, m), 6.95 (1H, s), 3.30-3.25 (2H, m),2.90-2.85 (1H, m), 2.80-2.75 (2H, m), 1.35 (6H, s), 0.95-0.90 (6H, m).33

δ_(H) (400MHz; CDCl₃): 8.05 (1H, s), 7.25 (1H, s), 7.05 (1H, s), 6.75(1H, br s), 3.40 (2H, m), 2.60 (2H, m), 2.50-2.30 (4H, m), 1.40-1.20(8H, m), 0.85 (6H, t). 34

δ_(H) (400MHz; CDCl₃): 7.85 (1H, s), 7.30-7.15 (5H, m), 7.10 (1H, s),7.05 (1H, s), 6.00 (1H, br s), 3.50 (2H, s), 3.25 (2H, m), 3.00 (1H, m),2.65 (2H, m), 1.10 (6H, d). 35

δ_(H) (400MHz; CDCl₃): 8.10 (1H, s), 7.30-7.20 (6H, m), 7.10 (1H, s),5.90 (1H, m), 3.50 (2H, s), 3.35 (2H, m), 2.90 (2H, m), 2.00 (2H, m),1.75-1.60 (3H, m), 1.40-1.30 (2H, m). 36

δ_(H) (400MHz; CDCl₃): 8.05 (1H, s), 7.25 (1H, s), 7.15-6.95 (5H, m),6.65 (1H, br s), 3.70 (2H, s), 3.60 (2H, m), 2.90 (2H, m), 2.75 (4H, m).37

δ_(H) (400MHz; CDCl₃): 8.25 (1H, s), 7.55 (1H, s), 7.00 (1H, s),3.45-3.35 (2H, m), 3.20-3.10 (2H, m), 2.70-2.65 (2H, m), 1.80-1.65 (4H,m), 1.65-1.30 (12H, m).

Preparation 38 N-Isopropylcyclopentanamine

[0397]

[0398] Pearlman's catalyst (20% w/w palladium hydroxide-on-carbon) (1.5g) was added to a solution of cyclopentylamine (15 ml, 0.21 mol) inacetone (200 ml). The reaction mixture was stirred under an atmosphereof hydrogen gas at 414 kPa (60 psi). After stirring for 16 hours thereaction mixture was filtered through Arbocel (Trade Mark) and thesolvent was removed under reduced pressure to give the title compound(15 ml) as a thin oil.

[0399] δ_(H) (400 MHz; CDCl₃): 3.20-3.10 (1H, m), 2.90-2.80 (1H, m),1.95-1.85 (2H, m), 1.75-1.45 (4H, m), 1.35-1.20 (2H, m), 1.10-1.00 (6H,m).

Preparation 39 [Cyclopentyl(isopropyl)amino]acetonitrile

[0400]

[0401] Hydroxyacetonitrile (8.2 ml of a 70% w/w solution in water, 0.1mol) was added to a solution of N-isopropylcyclopentanamine (11.43 g,0.09 mol) (Preparation 38) in ethanol (60 ml). The reaction mixture washeated under reflux for 3 hours, allowed to cool and evaporated underreduced pressure. The residue was purified by chromatography on silicagel eluting with dichloromethane:methanol (98: 2 by volume) to give thetitle compound (14.1 g) as a clear oil.

[0402] δ_(H) (400 MHz; CDCl₃): 3.60-3.50 (2H, s), 3.30-3.20 (2H, m),2.00-1.85 (2H, m), 1.80-1.55 (4H, m), 1.45-1.30 (2H, m), 1.15-1.05 (6H,m).

Preparation 40 [Isopropyl(1-methyl-1-phenylethyl)amino]acetonitrile

[0403]

[0404] The title compound was prepared fromN-isopropyl-2-phenyl-2-propanamine (Preparation 55) using a similarmethod to Preparation 39.

[0405] δ_(H) (400 MHz; CDCl₃): 7.55-7.45 (2H, m), 7.35-7.30 (2H, m),7.25-7.20 (1H, m), 3.60 (2H, m), 3.10-3.00 (1H, m), 1.60 (6H, m),1.10-1.05 (6H, m).

[0406] m/z MH⁺ 217.

Preparation 41 (2,2,6,6-Tetramethyl-1-iperidinyl)acetonitrile

[0407]

[0408] The title compound was prepared from2,2,6,6-tetramethylpiperidine using a similar method to that ofPreparation 39.

[0409] δ_(H) (400 MHz; CDCl₃): 3.45 (2H, s), 1.55-1.50 (4H, m), 1.10(12H, m).

Preparation 42

[0410] N′-Cyclopentyl-N¹-isopropyl-1,2-ethanediamine

[0411] Lithium aluminium hydride (66 ml of a 1 molar solution intetrahydrofuran, 0.066 mol) was added to a stirred solution of[cyclopentyl(isopropyl)amino]acetonitrile (10 g, 0.66 mol) (Preparation39) in tetrahydrofuran (100 ml) at 0° C. The reaction mixture wasstirred at 0° C. for 20 minutes and then heated under reflux for 2hours. The reaction mixture was allowed to cool to room temperature andleft to stand overnight. The reaction mixture was cooled in an icebathand treated dropwise with 4.8 ml of a 7.5% w/w aqueous sodium hydroxidesolution followed by 7.4 ml of water. The solvent was removed underreduced pressure and the residue was slurried with diethyl ether (200ml) for 30 minutes and then filtered. The filtrate was evaporated underreduced pressure to give the title compound as a colourless oil (10.30g).

[0412] δ_(H) (400 MHz; CDCl₃): 3.10-2.95 (2H, m), 2.70-2.60 (2H, m),2.50-2.40 (2H, m), 1.80-1.45 (10H, m), 1.05-0.95 (6H, m).

[0413] m/z MH⁺ 171.

Preparation 43 2-(2,2,6,6-Tetramethyl-1-Diieridinyl)ethanamine

[0414]

[0415] The title compound was prepared by a similar method to that ofPreparation 42 using (2,2,6,6-tetramethyl-1-piperidinyl)acetonitrile(Preparation 41).

[0416] δ_(H) (400 MHz; CDCl₃): 2.70-2.60 (2H, m), 2.50-2.40 (2H, m),1.60-1.40 (4H, m), 1.40-1.30 (4H, m), 1.00 (12H, s).

Preparation 44N¹-Isopropyl-N′-(1-methyl-1-phenylethyl)-1,2-ethanediamine

[0417]

[0418] The title compound was prepared by a similar method to that ofPreparation 42 using[isopropyl(1-methyl-1-phenylethyl)amino]acetonitrile (Preparation 40).

[0419] δ_(H) (400 MHz; CDCl₃): 7.55-7.50 (2H, m), 7.30-7.25 (2H, m),7.20-7.15 (1H, m), 2.90-2.80 (1H, m), 2.70-2.60 (4H, m), 1.35 (6H, m),0.95-0.90 (6H, m).

Preparation 45(2R,3R,4R,5R)-4-(Acetyloxy)-2-[(acetyloxy)methyl]-5-(6-chloro-2-cyano-9H-purin-9-yl)tetrahydro-3-furanylacetate

[0420]

[0421] Copper(I) cyanide was added to a solution of(2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(2,6-dichloro-9H-purin-9-yl)tetrahydro-3-furanylacetate (J. Med. Chem., 248, 35, 1992) (22 g, 40 mmol) inN′N′-dimethylformamide (150 ml). The suspension was heated to 100° C.for 2 hours and was then allowed to cool to room temperature. Thereaction mixture was poured into water (700 ml) with stirring. The solidwas filtered off and stirred in dichloromethane (700 ml) for 30 minutes.The solid was filtered off again and then stirred in dichloromethane(700 ml) for another 30 minutes. The dichloromethane portions werecombined and evaporated under reduced pressure to a volume of 500 ml.The dichloromethane was then dried over anhydrous sodium sulphate. Thesolvent was removed under reduced presure. The residue was redissolvedin dichloromethane (300 ml). The solvent was removed under reducedpressure. The residue was then stirred in diethylether (300 ml) for 20minutes. The solid was filtered off and dried to give the title compound(14.8 g).

[0422] δ_(H) (300 MHz; CDCl₃): 8.50 (1H, s), 6.10-6.05 (1H, m),5.80-5.75 (1H, m), 5.55-5.50 (1H, m), 4.55-4.50 (1H, m), 4.50-4.40 (2H,m), 2.20-2.15 (6H, m), 2.10 (3H, s).

Preparation 46(2R,3R,4S,5S)-2-(2-Amino-6-chloro-9H-purin-9-yl)-4-(benzoyloxy)-5-[(ethylamino)carbonyl]-tetrahydro-3-furanylbenzoate

[0423]

[0424] A suspension of 2-amino-6-chloropurine (4.60 g, 27.13 mmol) in1,1,1-trichloroethane (230 ml) was treated withN,O-bis(trimethylsilyl)acetamide (20 ml, 81.4 mmol). The mixture washeated under reflux for 6 hours. The solution was allowed to cool toroom temperature and the solvent was removed under reduced pressure. Theresidue was treated with a solution of(2S,3S,4R,5R)-5-(acetyloxy)-4-(benzoyloxy)-2-[(ethylamino)carbonyl]tetrahydro-3-furanylbenzoate and(2S,3S,4R,5S)-5-(acetyloxy)-4-(benzoyloxy)-2-[(ethylamino)carbonyl]tetrahydro-3-furanylbenzoate (Preparation 18) (14.39 g, 32.6 mmol) in anhydrous toluene (230ml) and trimethylsilyl trifluoromethanesulfonate (20 ml, 108.5 mmol).The resulting solution was then heated at 90° C. under a nitrogenatmosphere for 90 minutes. The mixture was cooled to room temperature,diluted with ethyl acetate (250 ml) and washed with a saturated aqueoussolution of sodium hydrogen carbonate (350 ml) and then brine (350 ml).The organic layer was separated, dried over anhydrous magnesiumsulphate, filtered and evaporated under reduced pressure. The residuewas purified by column chromatography on silica gel eluting withdichloromethane:methanol (98:2 by volume) to afford the title compoundas a foam (8.1 g).

[0425] m/z MH⁺ 552.

[0426] δ_(H) (⁴⁰⁰ MHz; CDCl₃): 8.10-7.95 (3H, m), 7.80 (2H, m),7.50-7.30 (6H, m), 6.90 (1H, m), 6.40-6.20 (3H, m), 5.20 (2H, br s),4.90 (1H, m), 3.45 (1H, m), 3.30 (1H, m), 1.15 (3H, t).

Preparation 47(2R,3R,4S,5S)-4-(Benzoyloxy)-2-(6-chloro-2-iodo-9H-purin-9-yl)-5-[(ethylamino)carbonyl]-tetrahydro-3-furanylbenzoate

[0427]

[0428] n-Butyl nitrite (4.65 ml, 39.7 mmol) was added to a suspension of(2R,3R,4S,5S)-2-(2-amino-6-chloro-9H-purin-9-yl)-4-(benzoyloxy)-5-[(ethylamino)carbonyl]-tetrahydro-3-furanylbenzoate (Preparation 46) (8.10 g, 14.7 mmol), iodine (3.73 g, 14.7mmol), copper(I) iodide (6.16 g, 32.3 mmol) and diiodomethane (12.55 ml,155.8 mmol) in THF (100 ml) and the mixture was heated under reflux for2.5 hours. The solution was allowed to cool to room temperature and thesolvent was removed under reduced pressure. The residue was partitionedbetween 5% w/w aqueous sodium metabisulfite solution (100 ml) anddichloromethane (100 ml). The organic layer was separated, filteredthrough Arbocel (Trade Mark), dried over anhydrous magnesium sulphateand evaporated under reduced pressure. The residue was purified bycolumn chromatography on silica gel eluting withdichloromethane:methanol (99:1 by volume) to afford the title compoundas a yellow foam (7.55 g).

[0429] m/z MNa⁺ 684.

[0430] δ_(H) 400 MHz; CDCl₃): 8.55 (1H, s), 8.05 (2H, m), 7.80 (2H, m),7.65-7.30 (6H, m), 6.75 (1H, m), 6.50 (1H, m), 6.10-6.00 (2H, m), 4.90(1H, m), 3.60-3.40 (2H, m), 1.25 (3H, t).

Preparation 48N-{2-[(1-Ethylpropyl)(isobutyl)amino]ethyl}-1H-imidazole-1-carboxamide

[0431]

[0432] A suspension of Pearlman's catalyst (200 mg) and benzyl2-[(1-ethylpropyl)(isobutyl)amino]ethylcarbamate (1.3 g, 4.06 mmol)(Preparation 49) in ethyl acetate (20 ml) was stirred under anatmosphere of hydrogen gas (414 kPa, 60 psi) at room temperature for 12hours. The reaction mixture was filtered through Arbocel (Trade Mark)and then the solvent was removed under reduced pressure. The crudematerial was dissolved in dichloromethane (10 ml) and the resultingsolution was added to a solution of N′N′-carbonyldiimidazole (0.66 g,4.10 mmol) in dichloromethane (10 ml). The reaction mixture was stirredat room temperature for 30 minutes and then diluted with dichloromethane(50 ml). The solution was washed with water (30 ml) and dried overanhydrous magnesium sulphate. The solvent was removed under reducedpressure and the residue was purified by column chromatography on silicagel eluting with ethyl acetate increasing in polarity to ethylacetate:methanol (97:3 by volume). This gave the title compound as a gum(0.5 g).

[0433] δ_(H) (400 MHz; CDCl₃): 8.05 (1H, s). 7.25 (1H, s), 7.10 (1H, s),6.45 (1H, bs), 3.45-3.40 (2H, m), 2.70-2.65 (2H, m), 2.45-2.40 (2H, m),2.30-2.20 (1H, m), 1.60-1.50 (1H, m), 1.50-1.20 (4H, m), 0.95-0.85 (12H,m).

Preparation 49 Benzyl 2-[(1-ethylpropyl)(isobutyl)amino]ethylcarbamate

[0434]

[0435] Sodium triacetoxyborohydride (1.87 g, 8.84 mmol) was added to asolution of benzyl 2-[(1-ethylpropyl)amino]ethylcarbamate (1.8 g, 6.8mmol) (Preparation 50), 3-methylbutanal (0.8 ml, 7.5 mmol) and aceticacid (1 ml, 8.85 mmol) in dichloromethane (50 ml). The reaction mixturewas stirred for 16 hours at room temperature. The reaction mixture wasdiluted with dichloromethane (50 ml) and then washed with saturatedaqueous sodium hydrogen carbonate solution (100 ml). The organic phasewas dried over anhydrous magnesium sulphate and then the solvent wasremoved under reduced pressure. The residue was purified by columnchromatography on silica gel eluting with dichloromethane methanol (95:5by volume) increasing in polarity to dichloromethane:methanol:0.88concentrated aqueous ammonia (95:5:0.5 by volume). This gave the titlecompound as an oil (1.3 g).

[0436] δ_(H) (400 MHz; CDCl₃): 7.40-7.25 (5H, m), 5.30-5.20 (1H, m),5.10-5.05 (2H, m), 3.25-3.15 (2H, m), 2.60-2.50 (2H, m), 2.45-2.35 (2H,m), 2.25-2.15 (1H, m), 1.65-1.50 (1H, m), 1.50-1.20 (5H, m), 1.00-0.80(12H, m).

Preparation 50 Benzyl 2-[(1-ethylpropyl)amino]ethylcarbamate

[0437]

[0438] Benzyl 2-aminoethylcarbamate hydrochloride (2 g, 8.65 mmol) wasdissolved in dichloromethane (50 ml) and 3-pentanone (3.7 ml, 35 mmol)was added. The reaction mixture was stirred for 1 hour at roomtemperature. Sodium triacetoxy borohydride (5.5 g, 26 mmol) was addedand the reaction mixture was then stirred for 16 hours at roomtemperature. The solution was washed with saturated aqueous sodiumhydrogen carbonate solution (40 ml). The dichloromethane phase was driedover anhydrous magnesium sulphate and the solvent was removed. Theresidues was purified by column chromatography on silica gel elutingwith dichloromethane methanol:0.88 concentrated aqueous ammonia(95:5:0.5 by volume). This gave the title compound as an oil (1.8 g).

[0439] δ_(H) (300 MHz; CDCl₃): 7.20-7.10 (5H, m), 5.30 (1H, bs), 5.10(2H, s), 3.35-3.20 (2H, m), 2.85-2.70 (2H, m), 2.40-2.30 (1H, m),1.50-1.30 (4H, m), 0.90-0.80 (6H, m).

Preparation 51 N¹,N¹-Dicyclopentyl-1,2-ethanediamine hydrochloride

[0440]

[0441] Hydrogen chloride gas was passed through a stirred ice coldsolution of tert-butyl 2-(dicyclopentylamino)ethylcarbamate (0.22 g,0.74 mmol) (Preparation 52) in dichloromethane (15 ml) until thesolution was saturated. The reaction mixture was allowed to warm to roomtemperature and then stirred for 1 hour. The solvent was removed underreduced pressure to give the title compound (0.15 g) as a brown foam.

[0442] m/z MH⁺ 197.

[0443] δ_(H) (400 MHz; CDCl₃): 10.80 (1H, s), 8.75 (3H, s), 3.80-3.60(6H, m), 2.25-1.50 (16H, m).

Preparation 52 tert-Butyl 2-(dicyclopentylamino)ethylcarbamate

[0444]

[0445] Iodocyclopentane (1.68 g, 8.6 mmol) was added to a suspension ofpotassium carbonate (1.8 g, 13.2 mmol) and tert-butyl2-[cyclopentylamino]ethylcarbamate (1.5 g, 6.6 mmol) (Preparation 53) inN′,N′-dimethylformamide (10 ml). The reaction mixture was stirred at 60°C. for 72 hours. The reaction mixture was allowed to cool and was thenpartitioned between ethyl acetate (50 ml) and water (50 ml). The ethylacetate layer was washed with brine (30 ml) and dried over anhydrousmagnesium sulphate. The solvent was removed to give a residue that waspurified by chromatography on silica gel eluting withdichloromethane:methanol (98:2 by volume) increasing in polarity todichloromethane:methanol:0.88 concentrated aqueous ammonia (90:10:1 byvolume) to give the title compound (64 mg) as a brown oil.

[0446] m/z MH⁺ 297.

[0447] δ_(H) (400 MHz; CDCl₃): 5.10-4.90 (1H, m), 3.30-3.05 (4H, m),2.65-2.50 (2H, m), 1.85-1.30 (25H, m).

Preparation 53 tert-Butyl 2-[cyclopentylamino]ethylcarbamate

[0448]

[0449] tert-Butyl 2-aminoethylcarbamate (3.0 g, 18.8 mmol) (Preparation54) was dissolved in cyclopentanone (30 ml). Pearlman's Catalyst (0.1 g)was added and the reaction mixture was stirred under an atmosphere ofhydrogen gas (414 kPa, 100 psi) for 48 hours. The catalyst was filteredoff through Arbocel (Trade Mark) and the solvent was removed underreduced pressure. The residue was purified by column chromatography onsilica gel eluting with dichloromethane:methanol:0.88 concentratedaqueous ammonia (95:5:0.5 by volume) increasing in polarity todichloromethane:methanol:0.88 concentrated aqueous ammonia (90:10:1 byvolume). The solvent was removed under reduced pressure to give thetitle compound (1.5 g) as an oil.

[0450] m/z MH⁺ 229.

[0451] δ_(H) (400 MHz; CDCl₃): 4.90 (1H, s), 3.25-3.10 (2H, m),3.05-2.95 (1H, m), 2.70-2.60 (2H, m), 1.85-1.75 (2H, m), 1.70-1.20 (17H,m).

Preparation 54 tert-Butyl 2-aminoethylcarbamate

[0452]

[0453] A solution of di(tert-butyl)dicarbonate (27.3 g, 0.125 mol) indichloromethane (100 ml) was added dropwise to a solution ofethylenediamine (30 g, 0.5 mol) over an hour. The reaction mixture wasstirred for a further hour at room temperature. The solvent was thenremoved under reduced pressure and the residue was partitioned betweenethyl acetate (600 ml) and 5% w/w aqueous sodium hydroxide solution (200ml). The ethyl acetate layer was washed with water (100 ml) and brine(100 ml) and dried over anhydrous sodium sulphate. The solvent wasremoved under reduced pressure to give the title compound as a whitesolid (19.1 g).

[0454] δ_(H) (60 MHz; CDCl₃): 3.30-2.60 (4H, m), 1.45-1.30 (9H, m),1.20-1.05 (2H, m).

Preparation 55 N-Isopropyl-2-phenyl-2-propanamine

[0455]

[0456] Sodium triacetoxyborohydride (4.5 g, 21.2 mmol) was addedportionwise to a solution of 1-methyl-1-phenylethylamine (0.96 g, 7.1mmol) in a mixture of acetone (5 ml) and dichloromethane (120 ml). Thereaction mixture was stirred at room temperature for 16 hours. Thesolvent was removed under reduced pressure and the residue waspartitioned between aqueous sodium hydroxide solution (2M, 100 ml) andethyl acetate (200 ml). The ethyl acetate layer was washed with water(100 ml) and brine (100 ml) and then dried over anhydrous magnesiumsulphate. The solvent was removed under reduced pressure to give thetitle compound (1 g) as a colourless oil.

[0457] δ_(H) (400 MHz; CDCl₃): 7.40-7.35 (2H, m), 7.30-7.20 (2H, m),7.15-7.10 (1H, m), 3.40 (1H, bs), 2.60-2.50 (1H, m), 1.40 (6H, s),0.90-0.85 (6H, m).

Preparation 56 2-[2-(4-Isopropyl-1-piperidinyl)ethyl]-1H-isoindole-13(2H)-dione

[0458]

[0459] A solution of 4-isopropylpiperidine (3.3 g, 20.2 mmol),N-(2-bromoethyl)phthalimide (5.4 g, 21.3 mmol), potassium carbonate (5.9g, 45.4 mmol) and acetonitrile (100 ml) and was heated under reflux for2.5 hours and then stirred at room temperature overnight. The solventwas removed under reduced pressure and the residue was partitionedbetween ethyl acetate (100 ml) and water (100 ml). The organic layer wasseparated and the aqueous layer was extracted with further ethyl acetate(100 ml). The combined organic extracts were dried over anhydrous sodiumsulphate and the solvent was removed by evaporation under reducedpressure. The resulting oil was purified by column chromatography onsilica gel eluting with a gradient system of dichloromethane changing todichloromethane:diethyl ether (50:50, by volume) changing to diethylether to afford the title compound (3.3 g).

[0460] m/z MH⁺ 301.

[0461] δ_(H) (400 MHz, CDCl₃): 7.80 (2H, m), 7.70 (2H, m), 3.80 (2H, t),3.00 (2H, m), 2.60 (2H, t), 1.95 (2H, m), 1.60 (2H, m), 1.40 (1H, m),1.20 (2H, qd), 0.95 (1H, m), 0.80 (6H, d).

Preparation 57 2-(4-Isopropyl-1-piperidinyl)ethylamine

[0462]

[0463] A solution of2-[2-(4-isopropyl-1-piperidinyl)ethyl]-1H-isoindole-1,3(2H)-dione(Preparation 56) (3.2 g, 10.6 mmol) in a 33 % w/w solution ofmethylamine in ethanol (60 ml) was heated under reflux for three hours.The solvent was removed under reduced pressure, more ethanol was added(60 ml) and the solvent was again removed under reduced pressure. Theresidue was suspended in dichloromethane (100 ml) and the solid wasfiltered off. This was washed with dichloromethane (100 ml). Thefiltrate was evaporated under reduced pressure and the resulting oil waspurified by column chromatography on silica gel eluting withdichloromethane:methanol:0.88 aqueous ammonia solution (90:10:1, byvolume) to give a colourless oil. Bulb-to-bulb distillation (150-160°C., 4 kPa) yielded the title compound (1.0 g, 55 %).

[0464] m/z MH⁺ 171.

[0465] δ_(H) (400 MHz; CDCl₃): 2.90 (2H, m), 2.80 (2H, t), 2.40 (2H, t),1.95 (2H, m), 1.65 (2H, m), 1.40 (1H, m), 1.30-1.20 (4H, m), 1.00 (1H,m), 0.85 (6H, d).

Preparation 58 N¹-(tert-Butyl)-N¹-cyclohexyl-1,2-ethanediamine

[0466]

[0467] Hydroxyacetonitrile (5.3 ml of of a 70% w/w solution in water, 32mmol) was added to a stirred solution of N-(tert-butyl)cyclohexanamine(5.3 ml, 32 mmol) in ethanol (50 ml) at room temperature. The reactionmixture was heated under reflux for 16 hours. The solution was allowedto cool to room temperature and the solvent was removed under reducedpressure. The residue was partitioned between dichloromethane (50 ml)and water (50 ml). The organic layer was dried over anhydrous magnesiumsulphate and the solvent was removed under reduced pressure. The cruderesidue was dissolved in tetrahydrofuran (30 ml) and a solution oflithium aluminium hydride in tetrahydrofuran (1M, 55 ml, 55 mmol) wasslowly added. The reaction mixture was heated under reflux for 2 hours.An aqueous solution of sodium hydroxide (2M, 6 ml) was then carefullyadded. The suspension was filtered and the liquid was concentrated underreduced pressure to give the title compound (3 g) as an oil.

[0468] δ_(H) (300 MHz; CDCl₃): 2.90-2.70 (1H, m), 2.70-2.55 (2H, m),2.20-1.95 (2H, m), 1.85-1.55 (4H, m), 1.40-1.15 (4H, m), 1.15-0.95 (11H,m).

Preparation 59(2R,3R,4R,5R)-4-(Acetyloxy)-2-[(acetyloxy)methyl]-5-(6-{[2,2-bis(4-methylphenyl)ethyl]amino}-2-cyano-9H-purin-9-yl)tetrahydro-3-furanylacetate

[0469]

[0470] The compound was prepared from(2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-chloro-2-cyano-9H-purin-9-yl)tetrahydro-3-furanylacetate (Preparation 45) and 2,2-bis(4-methylphenyl)ethanamine (J. Med.Chem., 1969, 12(1), 9) using a similar method to that of Preparation 64.

[0471] δ_(H) (400 MHz; CDCl₃): 7.95 (1H, s), 7.20-7.05 (8H, m),6.15-6.10 (1H, m), 5.95-5.90 (1H, m), 5.75-5.70 (1H, m), 5.55-5.50 (1H,m), 4.50-4.35 (3H, m), 4.30-4.20 (2H, m), 2.30 (6H, m), 2.20-2.00 (9H,m).

Preparation 60(2R,3R,4S,5R)-2-(2-(Aminomethyl)-6-{[2,2-bis(4-methylphenyl)ethyl]amino}-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol

[0472]

[0473](2R,3R,4R,5R)-4-(Acetyloxy)-2-[(acetyloxy)methyl]-5-(6-{[2,2-bis(4-methylphenyl)ethyl]amino}-2-cyano-9H-purin-9-yl)tetrahydro-3-furanylacetate (Preparation 59) (837 mg, 1.33 mmol) was dissolved in asaturated solution of ammonia in ethanol (25 ml). 10% Palladium oncarbon (168 mg) was added and the suspension was stirred under anatmosphere of hydrogen (414 kPa, 60 psi) for 16 hours. The reactionmixture was filtered through Arbocel (Trade Mark) and the filtrate wasevaporated under reduced pressure. The residue was dissolved in methanol(100 ml) and sodium carbonate (100 mg) was added. The suspension wasstirred at room temperature for 2 hours. The solvent was removed underreduced pressure and the residue was dissolved in a mixture ofdichloromethane (15 ml) and water (15 ml). The dichloromethane layer waswashed with water (15 ml) and saturated aqueous sodium chloridesolution. The solvent was removed under reduced pressure. The residuewas triturated with diethyl ether to give the title compound as a solid(340 mg).

[0474] m/z MH⁺ 503.

[0475] δ_(H) (400 MHz; CDCl₃): 8.10 (1H, s), 7.20-7.10 (4H, m),7.05-7.00 (4H, m), 5.90-5.85 (1H, m), 4.70-4.65 (1H, m), 4.40-4.35 (1H,m), 4.35-4.05 (3H, m), 3.85-3.80 (3H, m), 3.70-3.65 (1H, m), 2.05 (6H,m).

Preparation 61(2R,3R,4R,5R)-4-(Acetyloxy)-2-[(acetyloxy)methyl]-5-(6-{[2,2-bis(3-chlorophenyl)ethyl]amino}-2-cyano-9H-purin-9-yl)tetrahydro-3-furanylacetate

[0476]

[0477] The compound was prepared from(2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-chloro-2-cyano-9H-purin-9-yl)tetrahydro-3-furanylacetate (Preparation 45) and 2,2-bis(3-chlorophenyl)ethanamine (J. Med.Chem., 1988, 31(7), 1282) using a similar method to that of Preparation64.

[0478] δ_(H) (400 MHz; CDCl₃): 8.00 (1H, s), 7.30-7.10 (8H, m),6.20-6.10 (1H, m), 5.80-5.70 (1H, m), 5.60-5.50 (1H, m), 4.50-4.30 (4H,m), 4.30-4.15 (2H, m), 2.20-2.00 (9H, m).

Preparation 62(2R,3R,4S,5R)-2-(2-(Aminomethyl)-6-{[2,2-bis(3-chlorophenyl)ethyl]amino}-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol

[0479]

[0480] The title compound was prepared from(2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-{[2,2-bis(3-chlorophenyl)ethyl]amino}-2-cyano-9H-purin-9-yl)tetrahydro-3-furanylacetate (Preparation 61) by the method used in Preparation 60.

[0481] δ_(H) (400 MHz; CD₃OD): 8.15-8.10 (1H, m), 7.35-7.10 (8H, m),5.90-5.85 (1H, m), 4.70-4.65 (1H, m), 4.40-4.20 (3H, m), 4.10-4.05 (1H,m), 3.90-3.80 (3H, m), 3.70-3.65 (3H, m).

Preparation 63(2R,3R,4S,5R)-2-(2-(Aminomethyl)-6-{[2,2-bis(4-chlorophenyl)ethyl]amino}-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol

[0482]

[0483] A solution of(2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-{[2,2-bis(4-chlorophenyl)ethyl]amino}-2-cyano-9H-purin-9-yl)tetrahydro-3-furanylacetate (700 mg, 1 mmol) (Preparation 64) in ethanol (20 ml) wassaturated with ammonia gas. 10% Palladium on carbon (140 mg) was addedand the reaction mixture stirred under an atmosphere of hydrogen gas(414 kPa, 60 psi) at room temperature for 16 hours. The Palladium oncarbon was filtered off through Arbocel (Trade Mark) and the filtratewas evaporated under reduced pressure. The residue was dissolved inmethanol (50 ml) and sodium carbonate (60 mg, 0.57 mmol) was added. Thereaction mixture was stirred for 1.5 hours and then the solvent wasremoved under reduced pressure. The residue was purified by columnchromatography on silica gel eluting with dichloromethane:methanol:0.88concentrated aqueous ammonia (95:5:0.5 by volume) increasing in polarityto dichloromethane:methanol:0.88 concentrated aqueous ammonia (90:10:2by volume). The solvent was removed under reduced pressure to give thetitle compound (275 mg) as a foam.

[0484] m/z MH⁺ 545.

[0485] δ_(H) (400 MHz; CD₃OD): 8.10 (1H, s), 7.30-7.20 (8H, m),7.20-7.10 (1H, m), 5.90-5.85 (1H, m), 4.704.65 (1H, m), 4.50-4.40 (1H,m), 4.30-4.15 (3H, m), 4.15-4.10 (1H, m), 3.90-3.80 (3H, m), 3.70-3.65(1H, m).

Preparation 64(2R,3R,4R,5R)-4-(Acetyloxy)-2-[(acetyloxy)methyl]-5-(6-{[2,2-bis(4-chlorophenyl)ethyl]amino}-2-cyano-9H-purin-9-yl)tetrahydro-3-furanylacetate

[0486]

[0487] Triethylamine (0.2 ml, 1.14 mmol) was added to a stirred solutionof(2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-chloro-2-cyano-9H-purin-9-yl)tetrahydro-3-furanylacetate (500 mg, 1.14 mmol) (Preparation 45) and2,2-bis(4-chlorophenyl)ethanamine (919 mg, 1.2 mmol) (J. Am. Chem. Soc.,1983, 105(10), 3138) in acetonitrile (5 ml) at room temperature. Thereaction mixture was stirred for 16 hours. The solvent was then removedunder reduced pressure and the residue was dissolved in dichloromethane(20 ml). The solution was washed with water (10 ml) and saturated sodiumchloride solution (10 ml), dried over anhydrous magnesium sulphate andevaporated under reduced pressure. The residue was purified by columnchromatography on silica gel eluting with dichloromethane:methanol:(99:1by volume) increasing in polarity to dichloromethane:methanol (98.5:1.5by volume). The solvent was removed under reduced pressure to give thetitle compound (698 mg) as a foam.

[0488] m/z MH⁺ 667.

[0489] δ_(H) (400 MHz; CD₃OD): 7.95 (1H, s), 7.35-7.10 (8H, m),6.15-6.10 (1H, m), 5.95-5.85 (1H, m), 5.75-5.70 (1H, m), 5.55-5.50 (1H,m), 4.45-4.30 (4H, m), 4.30-4.10 (2H, m), 2.20-2.05 (9H, m).

Preparation 65(2R,3R,4S,5R)-2-(2-(Aminomethyl)-6-{[2,2-bis(3-methylphenyl)ethyl]amino}-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol

[0490]

[0491](2R,3R,4R,5R)-4-(Acetyloxy)-2-[(acetyloxy)methyl]-5-(6-{[2,2-bis(3-methylphenyl)ethyl]amino}-2-cyano-9H-purin-9-yl)tetrahydro-3-furanylacetate (620 mg, 1 mmol) (Preparation 66) was dissolved in a saturatedsolution of 0.88 concentrated aqueous ammonia in ethanol (20 ml). Thesolution was then stirred under an atmosphere of hydrogen gas (414 kPa,60 psi) at room temperature for 64 hours in the presence of 10%Palladium on carbon (120 mg). The reaction mixture was then filteredthrough Arbocel (Trade Mark) and the filtrate was evaporated to dryness.The residue was purified by column chromatography on silica gel elutingwith dichloromethane:methanol:(90:10 by volume) increasing in polarityto dichloromethane:methanol:0.88 concentrated aqueous ammonia (80:20:2by volume). The solvent was removed under reduced pressure to give thetitle compound (253 mg) as a foam.

[0492] m/z MH⁺ 503.

[0493] δ_(H) (400 MHz; CD₃OD): 8.10 (1H, s), 7.20-7.05 (6H, m),7.05-6.90 (2H, m), 5.95-5.90 (1H, m), 4.70-4.65 (1H, m), 4.40-4.35 (1H,m), 4.35-4.20 (2H, m), 4.20-4.10 (1H, m), 3.90-3.80 (2H, m), 3.70-3.65(1H, m), 2.05 (6H, m).

Preparation 66(2R,3R,4R,5R)-4-(Acetyloxy)-2-[(acetyloxy)methyl]-5-(6-{[2,2-bis(3-methylphenyl)ethyl]amino}-2-cyano-9H-purin-9-yl)tetrahydro-3-furanylacetate

[0494]

[0495] The title compound was prepared from(2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-chloro-2-cyano-9H-purin-9-yl)tetrahydro-3-furanylacetate (Preparation 45) and 2,2-bis(3-methylphenyl)ethanamine (J. Med.Chem., 1988, 31(7), 1282) using a similar procedure to that ofPreparation 64.

[0496] m/z MH⁺ 627.

[0497] δ_(H) (400 MHz; CD₃OD): 7.95 (1H, s), 7.25-7.15 (2H, m),7.10-7.00 (6H, m), 6.15-6.10 (1H, m), 5.95-5.90 (1H, m), 5.80-5.70 (1H,m), 5.60-5.55 (1H, m), 4.50-4.35 (3H, m), 4.30-4.20 (3H, m), 3.30 (6H,s), 2.20-2.05 (9H, m).

Preparation 67 (2R, 3R,4 S,5S)-4-(Benzoyloxy)-2-(6-{[2,2-bis(4-chlorophenyl)ethyl]amino}-2-iodo-9H-purin-9-yl)-5-[(ethylamino)carbonyl]tetrahydro-3-furanylbenzoate

[0498]

[0499] 2,2-Bis(4-chlorophenyl)ethanamine (426 mg, 1.51 mmol) (J. Am.Chem. Soc., 1983, 105(10), 3138) was added to a stirred solution of(2R,3R,4S,5S)-4-(benzoyloxy)-2-(6-chloro-2-iodo-9H-purin-9-yl)-5-[(ethylamino)carbonyl]tetrahydro-3-furanylbenzoate (500 mg, 0.755 mmol) (Preparation 47) in isopropyl alcohol (20ml) at room temperature. The reaction mixture was stirred at roomtemperature for 48 hours. The solvent was removed under reduced pressureto give a residue that was purified by column chromatography on silicagel eluting with dichloromethane:methanol:(99:1 by volume). The solventwas removed under reduced pressure to give the title compound (329 mg)as a foam.

[0500] m/z MH⁺ 891.

[0501] δ_(H) (400 MHz; CD₃OD): 8.10-8.00 (2H, m), 7.85-7.75 (3H, m),7.65-7.55 (1H, m), 7.55-7.40 (4H, m), 7.30-7.15 (8H, m), 6.30-6.20 (1H,m), 6.15-6.10 (1H, m), 6.10-6.05 (1H, m), 5.85-5.75 (1H, m), 4.90 (1H,s), 4.40-4.30 (2H, m), 4.25-4.10 (2H, m), 3.75-3.60 (1H, m), 3.60-3.45(1H, m), 1.30-1.20 (3H, m).

Preparation 68(2R,3R,4S,5S)-4-(Benzoyloxy)-2-(6-{[2,2-bis(4-chlorophenyl)ethyl]amino}-2-cyano-9H-purin-9-yl)-5-[(ethylamino)carbonyl]tetrahydro-3-furanylbenzoate

[0502]

[0503] Copper(I) cyanide was added to a solution of(2R,3R,4S,5S)-4-(benzoyloxy)-2-(6-{[2,2-bis(4-chlorophenyl)ethyl]amino}-2-iodo-9H-purin-9-yl)-5-[(ethylamino)carbonyl]tetrahydro-3-furanylbenzoate (440 mg, 0.494 mmol) (Preparation 67) in N′N′-dimethylformamide(10 ml). The reaction mixture was stirred at 90° C. overnight. Thereaction mixture was poured into water (15 ml). The precipitate wasfiltered off and stirred in dichloromethane (50 ml) for 10 minutes. Thedichloromethane was filtered, dried over anhydrous magnesium sulphateand evaporated under reduced pressure. The residue was purified bycolumn chromatography on silica gel eluting withdichloromethane:methanol (98: 2 by volume). The solvent was removedunder reduced pressure to give the title compound (227 mg) as a foam.

[0504] δ_(H) (400 MHz; CD₃OD): 8.20 (1H, m), 8.10-8.00 (3H, m),7,85-7.75 (2H, m), 7.65-7.60 (1H, m), 7.60-7.40 (4H, m), 7.35-7.15 (8H,m), 6.40-6.35 (1H, m), 6.30-6.20 (1H, m), 6.10-6.00 (2H, m), 4.90 (1H,m), 4.45-4.35 (1H, m), 4.30-4.15 (2H, m), 3.65-3.45 (2H, m), 1.30-1.20(3H, m).

Preparation 69(2S,3S,4R,5R)-5-{2-(Aminomethyl)-6-[(1-naphthylmethyl)amino]-9H-purin-9-yl}-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide

[0505]

[0506] 10% Palladium on carbon was added to a solution of(2R,3R,4S,5S)-4-(benzoyloxy)-2-{2-cyano-6-[(1-naphthylmethyl)amino]-9H-purin-9-yl}-5-[(ethylamino)carbonyl]tetrahydro-3-furanylbenzoate (487 mg, 0.71 mmol) (Preparation 70) dissolved in a saturatedsolution of ammonia in ethanol. The reaction mixture was stirred for 16hours under an atmosphere of hydrogen gas (414 kPa, 60 psi). Thereaction mixture was then filtered through Arbocel (Trade Mark) and thesolvent was removed under reduced pressure. The residue was purified bycolumn chromatography on silica gel eluting withdichloromethane:methanol:0.88 concentrated aqueous ammonia (95:5:0.5 byvolume) increasing in polarity to dichloromethane:methanol:0.88concentrated aqueous ammonia (80:20:2 by volume). The solvent wasremoved under reduced pressure to give the title compound (240 mg) as afoam.

[0507] δ_(H) (400 MHz; D₆DMSO): 8.45-8.20 (4H, m), 7.90-7.85 (1H, m),7.80-7.75 (1H, m), 7.55-7.45 (3H, m), 7.45-7.35 (1H, m), 5.95-5.90 (1H,m), 5.65-5.55 (1H, m), 5.55-5.45 (1H, m), 5.20-5.10 (2H, m), 4.65-4.55(1H, m), 4.25 (1H, s), 4.15-4.10 (1H, m), 4.10-3.90 (1H, m), 3.65 (2H,m), 3.20-3.00 (2H, m), 1.05-0.90 (3H, m).

Preparation 70(2R,3R,4S,5S)-4-(Benzoyloxy)-2-(2-cyano-6-[(1-naphthylmethyl)amino]-9H-purin-9-yl}-5-[(ethylamino)carbonyl]tetrahydro-3-furanylbenzoate

[0508]

[0509] Diazabicycloundecane (0.18 ml, 1.2 mmol) was added to a solutionof (6-[(1-naphthylmethyl)amino]-9H-purine-2-carbonitrile (200 mg, 0.67mmol) (Preparation 10) and(2S,3S,4R,5R)-5-(acetyloxy)-4-(benzoyloxy)-2-[(ethylamino)carbonyl]tetrahydro-3-furanylbenzoate and(2S,3S,4R,5S)-5-(acetyloxy)-4-(benzoyloxy)-2-[(ethylamino)carbonyl]tetrahydro-3-furanylbenzoate (309 mg, 0.70 mmol) (Preparation 18) in acetonitrile (5 ml).Trimethylsilyl trifluoromethanesulfonate (0.24 ml, 1.33 mmol) was addedand the reaction mixture heated under reflux for 30 minutes. Thereaction mixture was then allowed to cool to room temperature, dilutedwith ethyl acetate (20 ml) and washed twice with water (20 ml). Theethyl acetate layer was then washed with 10% w/w aqueous citric acid andsaturated aqueous sodium chloride solution (20 ml). The organic phasewas dried over anhydrous magnesium sulphate and evaporated under reducedpressure. The residue was purified by column chromatography on silicagel eluting with dichloromethane increasing in polarity todichloromethane:methanol (98:2 by volume). The solvent was removed underreduced pressure to give the title compound (235 mg) as a foam.

[0510] δ_(H) (400 MHz; d₆DMSO): 9.20-9.10 (1H, m), 8.75 (1H, m),8.30-8.20 (2H, m), 8.00-7.90 (3H, m), 7.80-7.70 (3H, m), 7.70-7.60 (1H,m), 7.60-7.30 (8H, m), 6.70-6.60 (1H, m), 6.30-6.20 (1H, m), 6.10-6.05(1H, m), 5.15-5.10 (2H, m), 4.90-4.85 (1H, m), 3.20-3.05 (2H, m),1.00-0.90 (3H, m).

Preparation 71(2R,3R,4R,5R)-4-(Acetyloxy)-2-[(acetyloxy)methyl]-5-{2-cyano-6-[(9H-fluoren-9-ylmethyl)amino]-9H-purin-9-yl}tetrahydro-3-furanylacetate

[0511]

[0512] Triethylamine (0.38 ml, 2.7 mmol) was added to a stirred solutionof(2R,3R,4R,5R)-4-(acetyloxy)-2-[(acetyloxy)methyl]-5-(6-chloro-2-cyano-9H-purin-9-yl)tetrahydro-3-furanylacetate (1.0 g, 2.3 mmol) (Preparation 45) and9H-fluoren-9-ylmethanamine (0.49 g, 2.5 mmol) (J. Org. Chem., 1971,36(23), 3539) in acetonitrile (30 ml) at room temperature. The reactionmixture was stirred at room temperature for 16 hours. The solvent wasremoved under reduced pressure. The residue was partially redissoved inethyl acetate (30 ml). The ethyl acetate was washed with water (1 ml)and a saturated aqueous sodium chloride solution (10 ml). The organicphase was evaporated under reduced pressure and the residue was purifiedby column chromatography on silica gel eluting with dichloromethane:ethyl acetate (96:4 by volume) increasing in polarity todichloromethane: ethyl acetate (94:6 by volume). The solvent was removedunder reduced pressure to give the title compound (1.23 g) as a foam.

[0513] m/z MH⁺ 595.

[0514] δ_(H) (300 MHz; CDCl₃): 8.00 (1H, s), 7.80-7.75 (2H, m),7.65-7.60 (2H, m), 7.45-7.30 (4H, m), 6.20-6.10 (1H, m), 6.05-5.95 (1H,m), 5.80-5.75 (1H, m), 5.60-5.55 (1H, m), 4.50-4.30 (4H, m), 4.30-4.20(2H, m), 2.20-2.05 (9H, m).

Preparation 72(2S,3S,4R,5R)-5-{6-[(2,2-Diphenylethyl)amino]-2-[(methylamino)methyl]-9H-purin-9-yl}-N-ethyl-3,4-dihydroxytetrahydro-2-furancarboxamide

[0515]

[0516] 10% Palladium on carbon (0.2 g) was added to a solution of(2S,3R,4R,5R)-4-(benzoyloxy)-5-{2-cyano-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-2-[(ethylamino)carbonyl]tetrahydro-3-furanylbenzoate (1.0 g, 1.4 mmol) (Preparation 7) in 33% w/w methylamine inethanol (75 ml). The reaction mixture was stirred under an atmosphere ofhydrogen gas (4414 kPa, 60 psi) for 16 hours at room temperature. Thesolid was filtered off and the solvent was removed from the filtrateunder reduced pressure. The residue was purified by flash chromatographyon silica gel eluting with dichloromethane:methanol:0.88 concentratedaqueous ammonia (95:5:0.5 by volume) increasing in polarity todichloromethane:methanol:0.88 concentrated aqueous ammonia (90:10:1 byvolume) to give the title compound (0.52 g) as a solid.

[0517] m/z MH⁺ 532.

[0518] δ_(H) (400 MHz; CDCl₃): 8.25 (1H, s), 7.35-7.20 (8H, m),7.20-7.10 (2H, m), 6.05-6.00 (1H, m), 4.55-4.45 (1H, m), 4.45 (2H, m),4.40-4.20 (2H, m), 3.80 (2H, m), 3.40-3.20 (2H, m), 2.45 (3H, m),1.15-1.05 (3H, m).

Preparation 73 N-[2-(1-Piperidinyl)ethyl]-1H-imidazole-1-carboxamide

[0519]

[0520] 2-(1-Piperidinyl)ethylamine (1.28 g, 10 mmol) was added to astirred solution of N,N′-carbonyldiimidazole (1.62 g, 10 mmol) in THF(25 ml) at room temperature. The reaction mixture was stirred overnightand the solvent was then removed by evaporation under reduced pressure.The residue was partitioned between ethyl acetate (100 ml) and water (50ml) and the ethyl acetate layer was separated, washed with brine (30 ml)and dried with anhydrous sodium sulphate. Evaporation of the solventunder reduced pressure yielded the title compound as a white solid (1.8g).

[0521] δ_(H) (400 MHz; CDCl₃): 8.10 (1H, s), 7.35 (1H, s), 7.10 (1H, s),6.80 (1H, br s), 3.45 (2H, m), 2.55 (2H, m), 2.50-2.30 (4H, m),1.60-1.40 (6H, m).

Pharmacological Activity

[0522] All the compounds of the Examples were tested foranti-inflammatory activity by their ability to inhibit neutrophilfunction (which indicates A2a receptor agonist activity) by the methoddescribed on page 42 and all had an IC₅₀ of less than 1 micromolar.

1-47. (canceled)
 48. A method of treating respiratory disease in amammal comprising administering to a mammal in need of such treatment(a) a compound of formula (I)

 a stereoisomer or solvate thereof, or a pharmaceutically acceptablesalt of said compound, stereoisomer, or solvate, wherein: R¹ and R² areeach independently hydrogen or methyl; X and Y together areCH₂—CH(OH)—Ar or CH₂—C(O)—Ar, or X is a covalent bond, NR³ or CHR⁴,wherein, R³ is (C₁-C₃)alkyl or a phenyl that is optionally substitutedwith one or more substituents selected from OH, F, Cl, Br, I, CN, CF₃,(C₁-C₆)alkyl, O—(C₁-C₆)alkyl, S(O)_(n)—(C₁-C₆)alkyl and SO₂—NR⁵R⁶, andR⁴ is hydrogen or methyl, and Y is a phenyl or naphthyl ring optionallysubstituted with one or more substituents selected from Ar, OH, F, Cl,Br, I, CN, CF₃, (C₁-C₆)alkyl, O—(C₁-C₆)alkyl, S(O)_(n)—(C₁-C₆)alkyl andSO₂—NR⁵R⁶; Ar is a phenyl or naphthyl ring optionally substituted withone or more substituents selected from F, Cl, Br, I, CN, CF₃,(C₁-C₆)alkyl, O—(C₁-C₆)alkyl, S(O)_(n)—(C₁-C₆)alkyl and SO₂—NR⁵R⁶; n isindependently for each occurrence 0, 1 or 2; R⁵ is independently foreach occurrence H, (C₁-C₆)alkyl, phenyl or naphthyl; and R⁶ isindependently for each occurrence (C₁-C₆)alkyl, phenyl or naphthyl; or,(b) a pharmaceutical composition comprising said compound of formula(I), said stereoisomer or solvate thereof, or said pharmaceuticallyacceptable salt of said compound, stereoisomer, or solvate; and apharmaceutically acceptable carrier, vehicle, or diluent.
 49. The methodof claim 48 wherein the disease is adult respiratory distress syndrome(ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonarydisease, cystic fibrosis, asthma, emphysema, bronchiectasis, chronicsinusitis or rhinitis.
 50. A method of treating inflammation in a mammalcomprising administering to a mammal in need of such treatment: (a) acompound of formula (I)

 a stereoisomer or solvate thereof, or a pharmaceutically acceptablesalt of said compound, stereoisomer, or solvate, wherein: R¹ and R² areeach independently hydrogen or methyl; X and Y together areCH₂—CH(OH)—Ar or CH₂—C(O)—Ar, or X is a covalent bond, NR³ or CHR⁴,wherein, R³ is (C₁-C₃)alkyl or a phenyl that is optionally substitutedwith one or more substituents selected from OH, F, Cl, Br, I, CN, CF₃,(C₁-C₆)alkyl, O—(C₁-C₆)alkyl, S(O)_(n)—(C₁-C₆)alkyl and SO₂—NR⁵R⁶, andR⁴ is hydrogen or methyl, and Y is a phenyl or naphthyl ring optionallysubstituted with one or more substituents selected from Ar, OH, F, Cl,Br, I, CN, CF₃, (C₁-C₆)alkyl, O—(C₁-C₆)alkyl, S(O)_(n)—(C₁-C₆)alkyl andSO₂—NR⁵R⁶; Ar is a phenyl or naphthyl ring optionally substituted withone or more substituents selected from F, Cl, Br, I, CN, CF₃,(C₁-C₆)alkyl, O—(C₁-C₆)alkyl, S(O)_(n)—(C₁-C₆)alkyl and SO₂—NR⁵R⁶; n isindependently for each occurrence 0, 1 or 2; R⁵ is independently foreach occurrence H, (C₁-C₆)alkyl, phenyl or naphthyl; and R⁶ isindependently for each occurrence (C₁-C₆)alkyl, phenyl or naphthyl or,(b) a pharmaceutical composition comprising said compound of formula(I), said stereoisomer or solvate thereof, or said pharmaceuticallyacceptable salt of said compound, stereoisomer, or solvate; and apharmaceutically acceptable carrier, vehicle, or diluent.
 51. A methodof stimulating an A2a receptor in a mammal comprising administering to amammal in need of such stimulation: (a) a compound of formula (I)

 a stereoisomer or solvate thereof, or a pharmaceutically acceptablesalt of said compound, stereoisomer, or solvate, wherein: R¹ and R² areeach independently hydrogen or methyl; X and Y together areCH₂—CH(OH)—Ar or CH₂—C(O)—Ar, or X is a covalent bond, NR³ or CHR⁴,wherein, R³ is (C₁-C₃)alkyl or a phenyl that is optionally substitutedwith one or more substituents selected from OH, F, Cl, Br, I, CN, CF₃,(C₁-C₆)alkyl, O—(C₁-C₆)alkyl, S(O)_(n)—(C₁-C₆)alkyl and SO₂—NR⁵R⁶, andR⁴ is hydrogen or methyl, and Y is a phenyl or naphthyl ring optionallysubstituted with one or more substituents selected from Ar, OH, F, Cl,Br, I, CN, CF₃, (C₁-C₆)alkyl, O—(C₁-C₆)alkyl, S(O)_(n)—(C₁-C₆)alkyl andSO₂—NR⁵R⁶; Ar is a phenyl or naphthyl ring optionally substituted withone or more substituents selected from F, Cl, Br, I, CN, CF₃,(C₁-C₆)alkyl, O—(C₁-C₆)alkyl, S(O)_(n)—(C₁-C₆)alkyl and SO₂—NR⁵R⁶; n isindependently for each occurrence 0, 1 or 2; R⁵ is independently foreach occurrence H, (C₁-C₆)alkyl, phenyl or naphthyl; and R⁶ isindependently for each occurrence (C₁-C₆)alkyl, phenyl or naphthyl or,(b) a pharmaceutical composition comprising said compound of formula(I), said stereoisomer or solvate thereof, or said pharmaceuticallyacceptable salt of said compound, stereoisomer, or solvate; and apharmaceutically acceptable carrier, vehicle, or diluent.
 52. A methodof treating septic shock, male erectile dysfunction, hypertension,stroke, epilepsy, cerebral ischaemia, peripheral vascular disease,post-ischaemic reperfusion injury, diabetes, rheumatoid arthritis,multiple sclerosis, psoriasis, allergic dermatitis, eczema, ulcerativecolitis, Crohns disease, inflammatory bowel disease, Heliobacterpylori-gastritis, non-Heliobacter pylori gastritis, non-steroidalanti-inflammatory drug-induced damage to the gastro-intestinal tract ora psychotic disorder, or promoting wound healing in a mammal comprisingadministering to a mammal in need of such treatment: (a) a compound offormula (I)

 or a pharmaceutically acceptable salt or solvate thereof, wherein: R¹and R² are each independently hydrogen or methyl; X and Y together areCH₂—CH(OH)—Ar or CH₂—C(O)—Ar, or X is a covalent bond, NR³ or CHR⁴,wherein, R³ is (C₁-C₃)alkyl or a phenyl that is optionally substitutedwith one or more substituents selected from OH, F, Cl, Br, I, CN, CF₃,(C₁-C₆)alkyl, O—(C₁-C₆)alkyl, S(O)_(n)—(C₁-C₆)alkyl and SO₂—NR⁵R⁶, andR⁴ is hydrogen or methyl, and Y is a phenyl or naphthyl ring optionallysubstituted with one or more substituents selected from Ar, OH, F, Cl,Br, I, CN, CF₃, (C₁-C₆)alkyl, O—(C₁-C₆)alkyl, S(O)_(n)—(C₁-C₆)alkyl andSO₂—NR⁵R⁶; Ar is a phenyl or naphthyl ring optionally substituted withone or more substituents selected from F, Cl, Br, I, CN, CF₃,(C₁-C₆)alkyl, O—(C₁-C₆)alkyl, S(O)_(n)—(C₁-C₆)alkyl and SO₂—NR⁵R⁶; n isindependently for each occurrence 0, 1 or 2; R⁵ is independently foreach occurrence H, (C₁-C₆)alkyl, phenyl or naphthyl; and R⁶ isindependently for each occurrence (C₁-C₆)alkyl, phenyl or naphthyl or,(b) a pharmaceutical composition comprising said compound of formula(I), said stereoisomer or solvate thereof, or said pharmaceuticallyacceptable salt of said compound, stereoisomer, or solvate; and apharmaceutically acceptable carrier, vehicle, or diluent.